Method and device for treating abnormal tissue growth with electrical therapy

ABSTRACT

This invention relates generally to the electrical treatment of malignant tumors and neoplasms by applying a voltage to affected tissue. Devices and various adaptations therein are described for use in electrical therapy. Additionally, various chemotherapeutic agent and radiation therapies are described which may be advantageously used in conjunction with electrical therapy to ameliorate cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/434,400 for “METHOD AN DEVICE FOR TREATING CANCER WITH ELECTRICALTHERAPY IN CONJUNCTION WITH CHEMOTHERAPEUTIC AGENTS AND RADIATIONTHERAPY,” which is a continuation-in-part (CIP) of U.S. Ser. No.09/974,474 for “IMPLATABLE DEVICE AND METHOD FOR THE ELECTRICALTREATMENT OF CANCER” filed Oct. 9, 2001, which is a continuation-in-part(CIP) of U.S. Ser. No. 09/524,405 for “IMPLATABLE DEVICE AND METHOD FORTHE ELECTRICAL TREATMENT OF CANCER” filed Mar. 13, 2000, all of whichare hereby incorporated by reference.

Application Ser. No. 10/434,400 also claims priority under 35 U.S.C. 30§119 (e) to provisional U.S. Ser. Nos. 60/377,840 for “PROGRAMMER ANDINSTRUMENT FOR ELECTROCHEMICAL CANCER TREATMENT” filed May 7, 2002,60/377,841 for “METHOD OF ELECTRICAL TREATMENT FOR CANCER IN CONJUNCTIONWITH CHEMOTHERAPY AN RADIOTHERAPY filed May 7, 2002; 60/378,209 for“LEAD CONDUIT METHOD FOR ECT THERAPY” filed May 7, 2002; 60/378,210 for“DIELECTRIC SENSOR FOR ELECTROCHEMICAL CANCER THERAPY” filed May 7,2002; 60/378,211 “INDIVIDUALLY IDENTIFIABLE ELECTRODES FORELECTROCHEMICAL CANCER THERAPY” filed May 7, 2002; 60/378,212 for“MULTIPLE TUMOR TREATMENT FOR CANCER BY ELECTRICAL THERAPY” filed May 7,2002; 60/378,213 for “PATIENT CONTROL FOR ELECTROCHEMICAL CANCERTHERAPY” filed May 7, 2002; 60/378,214 for “OPTICAL FIBER ECT SYSTEM FORPHOTOACTIVATED CYTOTOXIC DRUGS” filed May 7, 2002; 60/378,215 forSPECIALIZED LEAD FOR ELECTROCHEMICAL CANCER TREATMENT″ filed May 7,2002; 60/378,216 “THREE-AXIS ELECTRODE SYSTEM TO CHASE THE CENTER OFTUMOR MASS” filed May 7, 2002; 60/378,629 for “CLOSED LOOP OPERATION OFELECTROCHEMICAL TREATMENT FOR CANCER” filed May 9, 2002; 60/378,824 for“METHOD OF IMAGING BEFORE AND AFTER ELECTROCHEMICAL TREATMENT” filed May9, 2002; 60/379,793 for “ECT AN ELECTROPORATION ELECTRODE SYSTEM” filedMay 13, 2002; and 60/379,797 for “FIXATION MEANS LOCATED OUTSIDE TUMORMASS FOR ECT FOR CANCER” filed May 13, 2002, all of which are hereinincorporated by reference.

U.S. application Ser. No. 10/434,400 for “METHOD AN DEVICE FOR TREATINGCANCER WITH ELECTRICAL THERAPY IN CONJUNCTION WITH CHEMOTHERAPEUTICAGENTS AND RADIATION THERAPY” is also a continuation-in-part (CIP) ofU.S. Ser. No. 09/974,474 for “IMPLATABLE DEVICE AND METHOD FOR THEELECTRICAL TREATMENT OF CANCER” filed Oct. 9, 2001 under 35 U.S.C. §120,which is a non-provisional application claiming priority under 35 U.S.C.§119(e) to provisional U.S. Ser. Nos. 60/238,609 for “IMPLATABLETHERAPEUTIC DEVICE” filed Feb. 13, 2001, 60/238,612 for “ELECTROPHORETICDRUG INFUSION DEVICE” filed 15 Oct. 10, 2000, and 60/255,184 for “METHODFOR ELIMINATING POSSIBLE CORROSION OF ELECTRODES IN ELECTROCHEMICALTHERAPY AND ELECTROCHEMOTHERAPY” filed Dec. 12, 2000, all of which areherein incorporated by reference.

U.S. Ser. No. 09/974,474 for “IMPLATABLE DEVICE AND METHOD FOR THEELECTRICAL TREATMENT OF CANCER” filed Oct. 9, 2001 also claims priorityto 35 U.S.C. §120 as a CIP of U.S. Ser. No. 09/524,405 for “IMPLATABLEDEVICE AND METHOD FOR THE ELECTRICAL TREATMENT OF CANCER” filed Mar. 13,2000 under 35 U.S.C. §120, now U.S. Pat. No. 6,366,808, which claimspriority to provisional U.S. Ser. No. 60/128,505 for “IMPLATABLE DEVICEAND METHOD FOR THE ELECTRICAL TREATMENT OF CANCER” filed Apr. 9, 1999under 35 U.S.C. §119(e) all of which are herein incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the electrical treatment ofmalignant tumors and neoplasms by applying a voltage to affected tissue.Devices and various adaptations therein are described for use inelectrical therapy. Additionally, various chemotherapeutic agents andradiation therapies are described which may be advantageously used inconjunction with electrical therapy to ameliorate cancer.

2. Discussion of the Related Art

Cancer is one of the major causes of hospitalization and deathworldwide. However, many of the therapies applied to cancer treatmentare either ineffective or not well-tolerated by patients.

Cancer malignancies result in approximately 6,000,000 deaths worldwideeach year. In 1995, 538,000 cancer related deaths were reported in theUnited States, representing over 23% of the total deaths in the UnitedStates. This number has increased since 1970 when 331,000 deathsoccurred. The estimated number of new cases in the United States in 1997was 1,382,000. An astounding 40% of Americans will eventually bestricken with the disease and more than 1 in 5 will die from it. Thepercentage is increasing at about 1% per year and cancer deaths willsoon outstrip deaths from heart disease.

Much of the medical care cost associated with cancer results fromhospitalization. In 1994 there were 1,226,000 hospital discharges in theUnited States related to cancer treatment. The cost of cancer in termsof both human suffering and monetary expenditures is staggering.Effective treatment methods, which result in fewer days of hospitalcare, are desperately needed.

Primary treatment methods currently used in cancer therapy includesurgery, radiation therapy, chemotherapy, hormone therapy and manyothers including bone marrow replacement, biological response modifiers,gene therapy, and diet. Therapy often consists of combinations of thesetreatment methods. It is well known that these methods may result insickness, pain, disfigurement, depression, spread of the cancer, andineffectiveness. Despite recent announcements of potentialpharmaceutical “cures”, which may work well in animals and in humans incertain cases, researchers are cautious in overstating theireffectiveness. In the case of radiation treatment, rapid decreases inthe size of poorly differentiated tumors after treatment may beexperienced; however, shortly thereafter the tumor often experiencesre-growth. Unfortunately, following re-growth the tumor is generallymore insensitive to future radiation treatment attempts.

The approaches previously described, as well as other prior approaches,are not sufficient to meet the needs of real patients. The presentinvention addresses the above and other needs.

SUMMARY OF THE INVENTION

This invention relates generally to a method of treating cancer. Itinvolves a device, either partially or totally implanted, consisting ofa generator and one or more wires (or leads) containing one or moreelectrodes. The electrodes are implanted in or near the tumor and thegenerator may be implanted subcutaneously as close to the tumor aspractical. The device is powered either by an implantable generator orvia an external electrical source. The implantation is typicallyperformed under local anesthesia and the device is generally leftimplanted for a period of months. With implantation, the device permitselectric current to be applied at low levels for long periods of time.In another embodiment, the implanted device may be connected to anexternal device for energy input, data input, and/or therapy regimenmodifications. While the internal generator is useful for applying lowlevels of electrical current for long periods of time, the externalelectrical source may be advantageously used to generate high levels ofelectrical current over shorter periods of time. In a preferredembodiment the external generator may produce currents and pulses usefulin electroporation therapy. Additionally, methods and devices directedto chemotherapy and radiation therapy are described for use inconjunction with electrical therapy. In a preferred embodiment,electricity is provided in the form of direct current.

BRIEF DESCRIPTION OF THE DRAWINGS

The above mentioned and other objects and features of this invention andthe manner of attaining them will become apparent, and the inventionitself will be best understood by reference to the following descriptionof the embodiments of the invention in conjunction with the accompanyingdrawings, wherein:

FIG. 1 is a diagram depicting an overall system in accordance with oneembodiment;

FIG. 2 a-2 d are diagrams illustrating examples of unipolar andmultipolar lead placements suitable for use in an electrical therapysystem;

FIG. 2 e-2 f are schematic diagrams showing examples of circuitry forswitching electrode polarity, such as for use with an electrical therapysystem;

FIG. 2 g is a drawing illustrating an example of a multipolar leadplacement with an adapter, such as for use with an electrical therapysystem;

FIG. 3 a-3 c are drawings in front perspective, top view, and sideperspective illustrating an example of an array of multiple electrodeson a lead comprising a ring of electrodes, a separate top electrode, anda plurality of fixation needles that may be used with an electricaltherapy system;

FIG. 4 is a drawing in top view illustrating an example of an array ofmultiple electrodes on a lead comprising a ring of electrodes and afixation needle unattached to any electrode such as may be employed inan electrical therapy system;

FIG. 5 a-5 b are drawings in top view and side perspective illustratingan example of an array of multiple electrodes on a lead comprising aring of electrodes, a separate top electrode, and a single fixationneedle such as may be employed in an electrical therapy system;

FIG. 6 a-6 b are drawings in top view and side perspective illustratingan example of an array of multiple electrodes on a lead comprising aring of electrodes such as may be employed in an electrical therapysystem;

FIG. 7 a-7 b are diagrams shown in top view and side perspectiveillustrating an example of an array of multiple electrodes on a leadcomprising a ring of electrodes and an anchoring hook such as may beused with an electrical therapy system;

FIG. 8 a-8 b are illustrations in top view and side perspectivedepicting an example of an array of multiple electrodes on a leadcomprising a segment of electrodes not in closed ring formation and aplurality of fixation needles such as may be employed in an electricaltherapy system;

FIG. 9 is a diagram representing an example of an array of multipleelectrodes on a lead comprising adapters that may be used with anelectrical therapy system;

FIG. 10 a-10 b is an illustration depicting an example of an electrodearrangement which accommodates electrical therapy and electroporationsuch as may be employed in an electrical therapy system;

FIG. 11 is a drawing illustrating an example of three-axis electrodesystem such as may be employed in an electrical therapy system;

FIG. 12 a-12 b is a drawing depicting an example of a set of leads withunique identification markings that may be utilized with an electricaltherapy system;

FIG. 13 a-13 e are drawings showing examples of lead anchoring systemssuch as may be used with any of the leads described in FIG. 2 a-2 d,FIG. 2 g, FIG. 3 a-3 c, FIG. 4, FIG. 5 a-5 b, FIG. 6 a-6 b, FIG. 7 a-7b, FIG. 8 a-8 b, FIG. 9, FIG. 11, and FIG. 12 a-12 b;

FIG. 14 is an illustration depicting an example of a fixation means fordirectly anchoring a lead to healthy tissue that may be used with any ofthe leads described in FIG. 2 a-2 d, FIG. 2 g, FIG. 3 a-3 c, FIG. 4,FIG. 5 a-5 b, FIG. 6 a-6 b, FIG. 7 a-7 b, FIG. 8 a-8 b, FIG. 9, FIG. 11,and FIG. 12 a-12 b;

FIG. 15 is an illustration depicting an example of a fixation means forindirectly anchoring a lead to healthy tissue that may be used with anyof the leads described in FIG. 2 a-2 d, FIG. 2 g, FIG. 3 a-3 c, FIG. 4,FIG. 5 a-5 b, FIG. 6 a-6 b, FIG. 7 a-7 b, FIG. 8 a-8 b, FIG. 9, FIG. 11,and FIG. 12 a-12 b;

FIG. 16 is an illustration depicting an example of a lead with variousoptions including a lumen, non-stick surface, and an inflatable balloonthat may be used with any of the leads described in FIG. 2 a-2 d, FIG. 2g, FIG. 3 a-3 c, FIG. 4, FIG. 5 a-5 b, FIG. 6 a-6 b, FIG. 7 a-7 b, FIG.8 a-8 b, FIG. 9, FIG. 11, and FIG. 12 a-12 b;

FIG. 17 is a drawing illustrating an example of a lead with variousoptions including optical fibers and thermocouples that may be used withany of the leads described in FIG. 2 a-2 d, FIG. 2 g, FIG. 3 a-3 c, FIG.4, FIG. 5 a-5 b, FIG. 6 a-6 b, FIG. 7 a-7 b, FIG. 8 a-8 b, FIG. 9, FIG.11, and FIG. 12 a-12 b;

FIG. 18 is a drawing illustrating a side view of an example of a leadwith thermocouples that may be used with any of the leads described inFIG. 2 a-2 d, FIG. 2 g, FIG. 3 a-3 c, FIG. 4, FIG. 5 a-5 b, FIG. 6 a-6b, FIG. 7 a-7 b, FIG. 8 a-8 b, FIG. 9, FIG. 11, and FIG. 12 a-12 b;

FIG. 19 a-19 c is a drawing showing several examples of a lead modifiedfor measuring capacitance and resistance that may be used with any ofthe leads described in FIG. 2 a-2 d, FIG. 2 g, FIG. 3 a-3 c, FIG. 4,FIG. 5 a-5 b, FIG. 6 a-6 b, FIG. 7 a-7 b, FIG. 8 a-8 b, FIG. 9, FIG. 11,and FIG. 12 a-12 b;

FIG. 20-21 are representations of an example of a method and device forcreating a conduit for leads to pass through to a tumor for use inelectrical therapy systems;

FIG. 22 is a block representation of an exemplary basic generator suchas may be utilized in an electrical therapy system;

FIG. 23 is a block representation of an exemplary advanced generatorsuch as may be utilized in an electrical therapy system;

FIG. 24 is a block representation of an exemplary generator comprising aport such as may be utilized in an electrical therapy system;

FIG. 25 is an illustration depicting an example of a port for use in anelectrical therapy system;

FIG. 26 is an up close diagram of a needle inserted into a port duringelectrical therapy;

FIG. 27 a-27 f are flow charts representing exemplary methods of thepreferred embodiment;

FIG. 28 a-28 b are graphs representing exemplary current levels for usein electrical therapy;

FIG. 29 a-29 b are graphs representing exemplary current levels for usein electrical therapy;

FIG. 30 is a diagram representing exemplary therapeutic pathways in ahuman body during electrical therapy;

FIG. 31 is an illustration depicting an example of a generator/infusiondevice that infuses chemotherapeutic agents to a tumor such as may beemployed with an electrical therapy system;

FIG. 32 is an illustration depicting an example of a generator/infusiondevice that infuses chemotherapeutic agents to the circulatory systemsuch as may be employed in an electrical therapy system;

FIG. 33 is an illustration depicting an example of a drug infusiondevice that is physically separated from a generator such as may beutilized in electrical therapy systems;

FIG. 34 is a diagram representing an exemplary method of passivesynchronization which may be employed with an electrical therapy system;

FIG. 35 a-35 f are illustrations depicting several examples of cathetersused to infuse drugs at a target site such as may be employed with anelectrical therapy system;

FIG. 36 a-36 c are illustrations depicting examples of catheterscomprising porous drug-absorbing material, which can be laid out over atumor and may be employed with an electrical therapy system;

FIG. 37 a-37 c is a drawing illustrating an example of an electrodearray that can be used to steer or spread charged drugs in electricaltherapy systems;

FIG. 38 a-38 b is a drawing depicting an application of the electrodearray/catheter design of FIG. 37 a-37 c;

FIG. 39 (prior art) is an illustration of an example electrophoreticdrug pump such as may be used with any of the catheters described inFIG. 35 a-35 f and FIG. 36 a-36 c;

FIG. 40 is an a illustration depicting an application of theelectrophoretic drug pump of FIG. 39 into an electrical therapy system;

FIG. 41 a-41 b is an illustration representing an application of FIG.40, whereby the electrodes are in the form of bands arranged around thecircumference of a cylindrical implantable device for use in anelectrical therapy system;

FIG. 42 a-42 b is an illustration of a device for infusing a solidionized substance for increased conductivity and reduced impedance in atumor for use in an electrical therapy system;

FIG. 43 is an illustration depicting an example of a device fortreatment of tumors with an optical fiber such as may be employed in anelectrical therapy system;

FIG. 44 is side-view illustration depicting an example of a generatoruseful for providing power to a light source that activatesphotosensitive drugs in an electrical therapy system;

FIG. 45 is a graph depicting examples of time-varying characteristics ofan electrical pulse for use in an electrical therapy system;

FIG. 46 is a graph representing an exemplary method for use in with anelectrical therapy system;

FIG. 47 a-47 b is a drawing showing examples of redundant electrodesused to prevent adverse effects of corrosion in electrical therapy;

FIG. 48 is an illustration representing an example of a basic form of anexternal device for use with electrical therapy; and

FIG. 49 is an example of a user friendly data chart that can be used todisplay current information and to input changes to the controller of anexternal device used in electrical therapy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description is of the best mode presently contemplated forpracticing the invention. This description is not to be taken in alimiting sense, but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe ascertained with reference to the claims.

The devices and methods of the present embodiment are contemplated foruse in patients afflicted with cancer or other non-cancerous (benign)growths. These growths may manifest themselves as any of a lesion,polyp, neoplasm (e.g. papillary urothelial neoplasm), papilloma,malignancy, tumor (e.g. Klatskin tumor, hilar tumor, noninvasivepapillary urothelial tumor, germ cell tumor, Ewing's tumor, Askin'stumor, primitive neuroectodermal tumor, Leydig cell tumor, Wilms' tumor,Sertoli cell tumor), sarcoma, carcinoma (e.g. squamous cell carcinoma,cloacogenic carcinoma, adenocarcinoma, adenosquamous carcinoma,cholangiocarcinoma, hepatocellular carcinoma, invasive papillaryurothelial carcinoma, flat urothelial carcinoma), lump, or any othertype of cancerous or non-cancerous growth. Tumors treated with thedevices and methods of the present embodiment may be any of noninvasive,invasive, superficial, papillary, flat, metastatic, localized,unicentric, multicentric, low grade, and high grade.

The devices and methods of the present embodiment are contemplated foruse in numerous types of malignant tumors (i.e. cancer) and benigntumors. For example, the devices and methods described herein arecontemplated for use in adrenal cortical cancer, anal cancer, bile ductcancer (e.g. periphilar cancer, distal bile duct cancer, intrahepaticbile duct cancer) bladder cancer, benign and cancerous bone cancer (e.g.osteoma, osteoid osteoma, osteoblastoma, osteochrondroma, hemangioma,chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma,malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma,lymphoma, multiple myeloma), brain and central nervous system cancer(e.g. meningioma, astrocytoma, oligodendrogliomas, ependymoma, gliomas,medulloblastoma, ganglioglioma, Schwannoma, germinoma,craniopharyngioma), breast cancer (e.g. ductal carcinoma in situ,infiltrating ductal carcinoma, infiltrating lobular carcinoma, lobularcarcinoma in situ, gynecomastia), Castleman disease (e.g. giant lymphnode hyperplasia, angiofollicular lymph node hyperplasia), cervicalcancer, colorectal cancer, endometrial cancer (e.g. endometrialadenocarcinoma, adenocanthoma, papillary serous adenocarcinoma, clearcell) esophagus cancer, gallbladder cancer (mucinous adenocarcinoma,small cell carcinoma), gastrointestinal carcinoid tumors (e.g.choriocarcinoma, chorioadenoma destruens), Hodgkin's disease,non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer (e.g. renal cellcancer), laryngeal and hypopharyngeal cancer, liver cancer (e.g.hemangioma, hepatic adenoma, focal nodular hyperplasia, hepatocellularcarcinoma), lung cancer (e.g. small cell lung cancer, non-small celllung cancer), mesothelioma, plasmacytoma, nasal cavity and paranasalsinus cancer (e.g. esthesioneuroblastoma, midline granuloma),nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngealcancer, ovarian cancer, pancreatic cancer, penile cancer, pituitarycancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g.embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphicrhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma,nonmelanoma skin cancer), stomach cancer, testicular cancer (e.g.seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer(e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiatedcarcinoma, medullary thyroid carcinoma, thyroid lymphoma), vaginalcancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma).

Patients treated with the devices and methods of the present embodimentmay be any living thing, but preferably a mammal such as, but notlimited to, humans, monkeys, chimps, rabbits, rats, horses, dogs, andcats. Patients treated with the devices and methods of the presentembodiment may be of any age (e.g. infant, child, juvenile, adolescent,adult, and even pregnant women and their unborn fetus, such as in thecase of gestational trophoblastic disease).

The devices and methods of the present embodiment work to treatcancerous tumors by delivering electrical therapy continuously and/or inpulses for a period of time ranging from a fraction of a second toseveral days, weeks, and/or months to tumors. In a preferred embodiment,electrical therapy is direct current electrical therapy. For thepurposes of discussion herein, the term “direct current (DC) electricaltherapy” may be used interchangeably with “direct current (DC)ablation”. Additionally, for the purposes of discussion herein, the term“electrical therapy” may refer to any amount of coulombs, voltage,and/or current delivered to a patient in any period of time. Forexample, coulombs, voltage, and/or current used at levels sufficient forDC ablation (which are generally lower coulombs, voltage, and/or currentand longer periods of time) and coulombs, voltage, and/or current usedat levels sufficient for electroporation (which are generally highercoulombs, voltage, and/or current and shorter periods of time) are bothincluded in “electrical therapy”. Furthermore, “electroporation” (i.e.rendering cellular membranes permeable) as used herein may be caused byany amount of coulombs, voltage, and/or current delivered to a patientin any period of time sufficient to open holes in cellular membranes(e.g. to allow diffusion of molecules such as pharmaceuticals,solutions, genes, and other agents into a viable cell).

Delivering electrical therapy to tissue causes a series of biologicaland electrochemical reactions. At a high enough voltage, cellularstructures and cellular metabolism are severely disturbed by theapplication of electrical therapy. Although both cancerous andnon-cancerous cells are destroyed at certain levels of electricaltherapy, tumor cells are more sensitive to changes in theirmicroenvironment than are non-cancerous cells. Distributions ofmacroelements and microelements are changed as a result of electricaltherapy.

Electrical therapy produces various byproducts including hydrogen,oxygen, chlorine, and hydrogen peroxide. Hydrogen peroxide is known todestroy living tissues whereas the effect of the other reaction productson living tissues varies. The byproducts and changes in tissue thatresult from electrical therapy are differentially experienced throughoutthe tissue based on the positioning of the anode and cathode. Forexample, chlorine, which is a strong oxidant, is liberated at the anode,whereas hydrogen is liberated at the cathode. Additionally, theconcentration of chlorine ions is high around the anode while theconcentration of sodium and potassium ions is found to be higher aroundthe cathode. pH changes due to electrical therapy cause the tissuearound the anode to become strongly acidic, down to 2.1, while thetissue around the cathode becomes strongly basic, up to 12.9. Watermigrates from the anode to the cathode while fat moves from the cathodeto the anode, causing local hydration around the cathode and dehydrationaround the anode. Proteins may be denatured in electrical therapy. Forexample, hemoglobin is transformed into acidic hemoglobin around theanode and alkaline hemoglobin around the cathode.

Electrochemical reactions as a function of pH and electrode potentialcan be predicted by means of a Pourbaix diagram in AqueousSolutions—Pergamon Press, 1986—by Pourbaix, which is herein incorporatedby reference.

As is readily understood by those of ordinary skill in the art, thecoulomb (C) is the basic unit of charge (e.g. the magnitude of thecharge on an electron or a proton is 1.6×10-19 coulombs—where the chargeon an electron is negative and the charge on a proton is positive).Electrical therapy may be described as the application of voltage involts (V), current in amperes (A), and/or total coulombs (C) delivered.Voltage is a measure of force per unit of charge. Voltage causes charge(i.e. current) to flow in a particular direction. Current, is the ratethat charge passes through a medium. Moreover, charge delivered incoulombs is equal to the current level in amperes multiplied by the timein seconds (i.e. charge (C)=current (A)*time (s)). In a wire (or lead)current is carried by electrons. In extracellular fluid (such as in atumor), current may be carried by an ion in solution.

Although electrical therapy examples described hereinbelow may beexpressed in voltage (i.e. volts) and/or current (i.e. amperes), itshould be understood that by applying Ohm's law, which states thatvoltage and current are proportional (i.e. V=IR), the equivalent voltageto current or current to voltage may be calculated. The proportionalityconstant is the resistance (R) in the electrode/tissue system.Resistance is measured in Ohms (Ω) and is equal to one volt per ampere.Resistance is the property of a material to resist current flow. In theelectrical therapy system described herein, resistance may be caused byany number of factors including tumor density, tumor consistency, tumorvolume, tumor location, pharmaceuticals utilized, wire(s) (or lead)utilized, electrode(s) utilized, and patient characteristics such asweight, age, gender, and diet. Because resistances may change withlong-term electrical therapy, it may be advantageous to program thedevices of the present embodiment in terms of current instead ofvoltage. For example in DC ablation, if 10 mA are applied to a tumorwith a resistance of 100Ω the corresponding voltage is 1 V. However, if10 mA are applied to a tumor with a resistance of 25Ω the correspondingvoltage is 0.25 V. In another example consistent with electroporation,if 500 V are applied to a tumor with a resistance of 25Ω thecorresponding current is 10 A. However, if 500 V are applied to a tumorwith a resistance of 100Ω the corresponding current is 5 A.

Electrical therapy may also be described as total coulombs (C)delivered. As will be appreciated by those of ordinary skill in the art,describing electrical therapy in terms of total coulombs (C) deliveredcan apply to numerous ranges of volts and amperes dependent on theresistance of the system and the rate of delivery. Therefore, becauseresistance may vary widely from one tumor to another, each of theexamples of the preferred embodiments described herein are merelyexamples and are not limiting. In each situation resistance of a tumormay be measured prior to application of electrical therapy to determinethe appropriate voltage, current, and/or coulombs to be delivered.

For example, if a dose of 0.5 C is applied to a tumor the resultingvoltage and current varies dependent on the rate at which the charge isdelivered and the resistance of the system. If, for example, theresistance of the system is 100Ω and the rate of delivery is over 10seconds then the resulting current is 0.005 A (50 mA) and the resultingvoltage is 5 V. In some circumstances it may be advantageous to deliverthe charge over a longer time period such as in DC ablation. Forexample, it a dose of 25 C is applied to a tumor over 1 hour and theresistance is 100Ω then the resulting current is 0.007 A (7 mA) and theresulting voltage is 0.7 V. In electroporation, electrical therapy isdelivered over a short time period. For example, if 1 mC is applied to atumor over 1 ms and the resistance is 1000Ω then the resulting voltageis 1000 V and the resulting current is 1 A.

With regard to the preferred methods of the embodiment, single electrodeand/or multi-electrode configurations of the preferred embodiment may beused in conjunction with electrical therapy regimens.

In the case of a single electrode configuration, high voltage may beapplied for minutes to hours between a lead electrode and the generatorhousing, which generates a pH change of at least 2 in either directionto begin destruction of cancerous tissue. Following application of highvoltage, a rest period, marked by idling of the device, is optionallyentered. Later, low voltage is applied for hours to days, which mayattract white blood cells to the tumor site. In this way, the cellmediated immune system may remove dead tumor cells and may developantibodies against tumor cells. Furthermore, the stimulated immunesystem may attack borderline tumor cells and metastases. Molecularchlorine generated at the anode may kill additional local tumor cells.

Various adjuvants may be used to increase any immunological response,depending on the host species, including but not limited to Freund'sadjuvant (complete and incomplete), mineral salts such as aluminumhydroxide or aluminum phosphate, various cytokines, surface activesubstances such as lysolecithin, pluronic polyols, polyanions, peptides,oil emulsions, and potentially useful human adjuvants such as BCG(bacille Calmette-Guerin) and Corynebacterium parvum. Alternatively, theimmune response could be enhanced by combination and or coupling withmolecules such as keyhole limpet hemocyanin, tetanus toxoid, diphtheriatoxoid, ovalbumin, cholera toxin or fragments thereof.

In the case of a multi-electrode configuration, high voltage may beapplied for minutes to hours between a first set of one or moreelectrodes and either a second set of one or more other electrodes, orthe generator housing.

In any case, high voltage may be applied for minutes to hours between atleast one anode and at least one cathode.

Any number and configuration of electrodes comprising either anodes orcathodes, or anodes and cathodes may be used.

In some embodiments the generator housing serves as either an anode or acathode.

As with the single electrode configuration, the high voltage appliedbetween at least one anode and at least one cathode generates a pHchange of at least 2 in either direction to begin necrosis. Followingapplication of high voltage, a rest period, marked by idling of thedevice, is optionally entered. Later, low voltage is applied for hoursto days, which may attract white blood cells to the tumor site. In thisway, the cell mediated immune system may remove dead tumor cells and maydevelop antibodies against tumor cells. Furthermore, the stimulatedimmune system may attack borderline tumor cells and metastases.

As previously described, various adjuvants may be used to increase anyimmunological response.

Additionally, electrical therapy may be used in conjunction withchemotherapy and radiation therapy. Steps relating to single electrodeand/or multi-electrode therapies may be followed by steps specificallydesigned for chemotherapy and radiation therapy.

In the case of electrical therapy used in conjunction with chemotherapy,at least one remote cathode may be implanted near a chemotherapyadministration site, or other site if the chemotherapy agent isadministered systemically. Next, a chemotherapy agent is administered.Following administration of a (positively charged) chemotherapeuticagent, medium voltage is applied between at least one anode (e.g. thegenerator housing or first electrode coupled to the generator housing bya first lead) and at least one remote cathode (e.g. an electrode coupledto the generator by a lead or second electrode coupled to the generatorby a second lead) to direct a chemotherapeutic agent to the tumor site.Alternatively, medium voltage may be applied between at least onecathode and at least one remote anode to direct a chemotherapeutic agentto the tumor site. Following the medium voltage step, the polarity ofthe generator housing (or first electrode) may switch with the polarityof the electrode (or second electrode) such that the generator housing(or first electrode) becomes cathodic and the electrode (or secondelectrode) becomes anodic. By reversing polarity of the generatorhousing (or first electrode) and electrode (or second electrode), thechemotherapeutic agent is dispersed throughout the peripheral tumormass. Following polarity reversal, electroporation electrical therapymay be optionally administered to the tumor site in order to increasepermeability of the cells to allow enhanced uptake of a chemotherapeuticagent. As is described hereinbelow, the devices and methods of thepresent embodiment may be adjusted for other variations, such as in thecase of a negatively charged chemotherapy agent.

In the case of electrical therapy used in conjunction with radiationtherapy, following the electrical therapy regimen as described forsingle electrode and/or multi-electrode configurations of the preferredembodiment, high voltage is applied to all electrodes, thereby forcingall electrodes anodic, for minutes to generate molecular oxygen.Alternatively, various substances may be administered to oxygenatetissue, as described hereinbelow. In this embodiment, localizedhyperoxia significantly increases brachytherapy effectiveness. As such,brachytherapy may be applied concomitantly to enhance the effects ofelectrical therapy.

Each of the previously described methods and method steps therein may beused in conjunction with each other for increased effectiveness. Forexample, chemotherapy and radiation therapy may be used in conjunctionwith the methods for unipolar and/or bipolar treatments.

Complexity of the device and therapeutic regimen can vary considerably,depending upon its desired flexibility of use. The device in itssimplest form may consist of a single lead permanently connected to agenerator encapsulated in plastic or potting compound (with an embeddedgenerator housing electrode) with a fixed DC output voltage.Alternatively, a complicated device may have numerous options andconfigurations ideal for any particular situation. Examples of thenumerous options and configurations suitable for implementing variousembodiments are described in full detail hereinbelow. A therapeuticregimen in its simplest form may consist of a single voltage applied toa single electrode for an amount of time. However, many complicatedtherapeutic regimens are also contemplated. Examples of the types ofcomplex therapeutic regimens suitable for implementing variousembodiments are apparent in the following description.

The cancer therapy system of several embodiments differs fromimplantable pacemaker systems in various ways. For example, pacemakersare generally implanted for years while the device of such embodimentsis typically implanted for months, until the cancerous condition hasbeen ameliorated. The cancer therapy system described herein is notlife-supporting as opposed to pacemakers, which are relied on bypatients to stimulate their heartbeat. The generator housing of cancertherapy systems may have lower hermeticity requirements (i.e. higherleak rate tolerance) in comparison to hermeticity requirements ofhousings used with pacemaker generators because the device of thepresent embodiment is designed to be implanted for months not years. Theleads of the present embodiment may have less stringent mechanicalrequirements since they are not stressed by movement (such as by themovement created by a beating heart) to the degree of pacemakers and arerequired for shorter periods of time, again months not years.Additionally, in most cases electromagnetic interference is not aconcern with the cancer therapy system of the present embodiment as itis with pacemaker systems. However, electromagnetic interference may bea concern in the case of highly specialized systems wherein certainsensors are employed.

Referring now to the drawings, further features and embodiments are nowdescribed.

1. OVERVIEW OF DEVICE

In FIG. 1, a system 1000 of the present embodiment for treating canceris depicted. The system 1000 comprises a generator 1, one or moreimplanted wires or leads 2 and 1616, an anode electrode 3, a cathodeelectrode 4, and an external instrument 5. The generator 1 and the leads2 and 1616 are implanted into a body 7 in a subcutaneous area as near aspractical to a tumor 6, but out of a path of any potentially plannedionizing radiation. The leads 2 and 1616 may terminate with either ananode electrode 3 or a cathode electrode 4. The anode electrode 3 andthe cathode electrode 4 are implanted inside or outside of the tumor 6.In a preferred embodiment, the anode electrode 3 is implanted in thecenter of the tumor 6 and the cathode electrode 4 is implanted outsidethe tumor 6 as shown, or in the tumor's internal periphery (i.e. in thevicinity of a cancerous tumor). The leads 2 and 1616 are tunneledsubcutaneously from the generator 1 to the tumor 6. The lead 1616terminating with the cathode electrode 4 may be alternatively placedinto a blood vessel (not shown) near tumor 6. The system 1000 may alsocomprise an external instrument 5 used to communicate with the generator1. The external instrument 5 is operably coupled to the generator 1 viacoupling means, which coupling means may be physical and/or telemetricand may include any of a universal serial bus (USB), a serial port, aPersonal Computer Memory Card International Association (PCMCIA) card,and a radio frequency (RF). The external instrument 5 may alter variousparameters including rate, intensity, and duration of therapy. Theexternal device 5 of the embodiment allows for inputting of data ormanipulating of therapy non-invasively.

2. LEADS

FIG. 2 a-2 d and FIG. 2 g depict various options for leads to be usedwith the cancer therapy system of the present embodiment. Shown in FIG.2 a-2 d and FIG. 2 g are the generator 1; the tumor 6; a unipolar lead8; a single electrode 9; a multipolar lead 10; two or more electrodes 11and 12; multiple unipolar leads 13 and 14; multiple multipolar leads 15,16, 17, and 25; multiple electrodes 18, 19, 20, 21, 22, and 23; anadapter 24; lead extensions 26 and 27; a same electrical connection 28;a common lead segment 1001; and a different electrical connection 1002.

In FIG. 2 a, the unipolar lead 8 is depicted. The unipolar lead 8 ofFIG. 2 a may be permanently coupled to a generator 1 such as with ahermetic feedthrough or may, alternatively, be coupled with a detachablecoupling means such as a hermetically sealed and/or biocompatible plugand socket connector. In any case, the unipolar lead 8 is operablycoupled to the generator 1 such that the unipolar lead 8 is energizedwhen the generator 1 is activated, thereby energizing electrode 9 aswell. The end of the unipolar lead 8, opposite the generator 1,terminates with the single electrode 9. The single electrode 9 may beimplanted in or adjacent to a tumor 6. In this case, the electrode 9 isshown implanted inside the tumor 6. In a preferred embodiment, theunipolar lead 8 terminates with an anode electrode while the generatorhousing serves as the cathode electrode. Alternatively, the unipolarlead 8 may terminate with a cathode electrode while the generatorhousing serves as the anode electrode. In a preferred embodiment, thegenerator 1 contains internal circuitry so that the polarity of theunipolar lead 8 and the polarity of the generator 1 may switch. Forexample, in the case that therapy begins with the unipolar lead 8serving as an anode and the generator housing 1 serving as a cathode,later, after a time period, internal circuitry may switch the polarityso that the unipolar lead 8 serves as the cathode and the generatorhousing 1 serves as the anode.

FIG. 2 b shows a multipolar lead 10. The multipolar lead 10 of FIG. 2 bis operably coupled, either permanently or detachably, at one end withthe generator 1 and terminates with the two or more electrodes 11 and12, which may be implanted in or adjacent to (i.e. in the vicinity of)the tumor 6 such that when the generator 1 is activated, energy flowsfrom the generator 1 through the multipolar lead 10 and to the two ormore electrodes 11 and 12 which are then consequently energized. Theelectrodes 11 and 12 may interchangeably serve as the anode and thecathode. For example, at the beginning of treatment, the electrode 11may be designated as the anode while the electrode 12 may be designatedas the cathode, or vice versa. Then, during therapy, the polarity of theelectrodes may change (reverse), such that the electrode 11 becomes thecathode and the electrode 12 becomes the anode. In another embodiment,both electrodes 11 and 12 of the lead may simultaneously serve as anodeswhile the generator housing serves as the cathode, or vice versa, andtheir polarities may change.

In FIG. 2 c, multiple unipolar leads 13 and 14 are operably coupled,either permanently or detachably, at one end to the generator 1 andterminate at the end opposite the generator 1 with one or moreelectrodes 11 and 12. In this embodiment, the electrodes 11 and 12 areimplanted adjacent to the tumor 6. However, in another embodiment, theelectrodes 11 and 12 may be implanted into the tumor 6. The electrodes11 and 12 each may serve as either an anode or a cathode (and may changepolarity as described above). In another embodiment, both electrodes 11and 12 may simultaneously serve as anodes while the generator housingserves as the cathode, or vice versa, and their polarities may change.

Referring now to FIG. 2 d, three multipolar leads 15, 16, and 17 areshown. Each of the multipolar leads 15, 16, and 17 are operably coupledat one end to the generator 1. The multipolar leads 15, 16, and 17 maybe permanently coupled to the generator 1 or may, alternatively, becoupled with a detachable means, such as described hereinabove. At theend of the multipolar leads 15, 16, and 17, opposite the generator 1,the multipolar leads 15, 16, and 17 terminate with multiple electrodes18, 19, 20, 21, 22, and 23 (including tip electrodes 19, 21, 23 and ringelectrodes 18, 20, 22). In one embodiment, the multiple electrodes 20and 21 are anode electrodes and the multiple electrodes 18, 19, 22, and23 are cathode electrodes. In another embodiment, the ring electrodes20, 18, and 22 may each serve as an anode while the tip electrodes 21,19, and 23 may each serve as a cathode, or vice versa. However, themultiple electrodes 18, 19, 20, 21, 22, and 23 may function in anycombination of anodes and cathodes.

Internal circuitry permits electrode switching as previously described.Turning now to FIG. 2 e-2 f, a hex bridge 300 which may beadvantageously used in conjunction with the embodiments described hereinis illustrated. Shown are a hex bridge 300; current source 249 with thepositive output shown on top; switches 240, 241, 242, 243, 244, and 245;electrodes 246 and 247; and a generator housing 248. By opening andclosing switches 240, 241, 242, 243, 244, and 245, electrodes 246, 247,and the generator housing 248 may be switched from an anode to a cathodeor vice versa. For example, by closing switch 240 and switch 243,current flows from the current source 249 through the switch 240 to theelectrode 246 then passes through tissue (not shown) to the electrode247, through the switch 243 and back to the current source 249. In thisexample, the electrode 246 serves as an anode while the electrode 247serves as a cathode. In another example, by opening the switch 240, andthe switch 243, and by closing switch 242 and switch 241, electricityflows from the current source 249 through the switch 242 to theelectrode 247, then passes through the tissue to the electrode 246through the switch 241 and back to the current source 249. In thisexample, the electrode 247 serves as the anode and the electrode 246serves as the cathode.

As illustrated by the previous two examples, the electrode 246 may serveas either the anode or the cathode and the electrode 247 may serve as ananode or a cathode. The electrodes 246, 247 may be electrodes ofseparate unipolar leads, or may be tip and ring electrodes of a bipolarelectrode.

As will be appreciated by those of ordinary skill in the art, numerousconfigurations of anode(s) and cathode(s) based on these principles maybe achieved by the type of circuit illustrated in FIG. 2 e-2 f. Forexample, both of the electrodes 246, 247 may be configured as the anodeor both of the electrodes 246, 247 may be configured as the cathode.And, in a similar manner, the generator housing 248 can be selectivelyconfigured as the anode or the cathode, either in addition to or insteadof one of the electrodes 246, 247. Importantly, the circuit asillustrated in FIG. 2 e-2 f may have any number of switches and anycombination of such switches may be closed or opened to treat tumorswith electrical therapy. The switches described hereinabove may bediscrete, or solid state and/or software controlled or electronicallycontrolled. Furthermore, any number of electrodes and configurations arecontemplated by the inventors. For example, as shown in FIG. 2 f, anynumber of electrodes may be coupled to the hex bridge 300 electricallybetween switch 242 and switch 244 and electrically between switch 243and switch 245, as is indicated by dashed lines. The electrodes of FIG.2 f, like the electrodes of FIG. 2 e, may be of any configuration,especially such as those described herein.

Looking now to FIG. 2 g, a common lead segment 1001 of the presentembodiment comprising a lead adapter 24 is shown. The lead adapter 24 ofthis embodiment allows the lead extensions 26 and 27 to enter thegenerator 1 via the common lead segment 1001 at the same electricconnection 28. The lead 25 enters the generator 1 in a differentelectric connection 1002 than lead extensions 26 and 27. The leadadapter 24 permits the use of additional leads such as lead extensions26 and lead 27 under certain circumstances. The lead adapter 24 may beadvantageously used when a large tumor and/or multiple tumors are beingtreated by a single generator 1. Importantly, the lead adapter 24 allowsfor adaptation during implantation or treatment. If, for example, anadditional tumor is formed or found at a later date than at initialimplant of the device of the preferred embodiment, use of the leadadapter 24 (or multiple lead adapters) allows flexibility in theimplanted device. Adjusting the number of leads via a lead adapter maybe preferable to extricating and replacing the entire implanted deviceor adding an additional implanted device. Leads used in conjunction withthe lead adapter 24 may be unipolar and multipolar, anode and cathode,may contain any number of electrodes, and may be placed internally andexternally relative to a tumor or both internally and externally. Thelead adapter 24 may take on any form useful to electrically couplecurrent from two or more leads to the same electric connection 28.However, in a preferred embodiment, the adapter may be shaped like a“Y.”

Many variations of lead configurations are possible and, likewise,possibilities of electrode placement are equally numerous. The above arebut a few examples of the types of lead configurations and electrodeplacements possible. As shown above, the leads of the present embodimentmay be multipolar and unipolar and of various lengths, sizes, andshapes. Furthermore, the leads may terminate with electrodes that areanode and/or cathode, and be implanted into, adjacent to, and/or in theinternal periphery of a tumor. In any event, the electrodes and leads ofthe preferred embodiment should be configured so that an electric fieldencompasses as much of the tumor as possible (or alternatively a targetportion of the tumor) while excluding the majority of the surroundingtissue.

Depicted in FIG. 3 a-3 c is an electrode array 310. Shown are theelectrode array 310; a tumor 6; a wire bundle 29; insulated wire segment30; electrodes 31, 32, 33, 34, and 35; needles 36; and insulated wirering 1003. FIG. 3 a is a front perspective of the electrode array 310wherein the entire mass of the tumor 6 is surrounded by the electrodes31, 32, 33, 34, 35. The electrode 31 is placed at the top of the tumor 6via insulated wire segment 30, while electrodes 32, 33, 34, and 35surround the tumor 6 via insulated wire ring 1003. The electrode 35 isdepicted behind the tumor 6 and is therefore not visible from theperspective of FIG. 3 a. The electrodes 32, 33, 34, and 35 are coupledtogether in a ring via insulated wire ring 1003. The electrode 34 iscoupled to a distal end of the wire bundle 29. The electrode 31 iselectrically coupled to the wire bundle 29 via the insulated wiresegment 30 through the electrode 34. A proximal end of the wire bundle29 is coupled to a generator (such as in FIG. 1) which provideselectrical therapy to the electrodes 31, 32, 33, 34, and 35. Currentpaths can be switched by the generator (not shown), such as by usingcircuitry similar to that depicted in FIG. 2 e-2 f, so that a currentpulse can flow from the electrode 35 to the electrode 31, then from theelectrode 34 to the electrode 31, then from the electrode 33 to theelectrode 31, then from the electrode 32 to the electrode 31, and so onin any sequence by delivering pulses of current between successive pairsof the electrodes 31 and a remaining one of the electrodes 32, 33, 34,and 35. Each electrode is fixed to tissue via the needles 36, which mayor may not serve as part of the electrode. The electrodes 31, 32, 33,34, and 35 may selectively comprise any combination of anodes andcathodes. In another embodiment, all of the electrodes 31, 32, 33, 34,and 35 may simultaneously serve as anodes while the generator housing(not shown) serves as the cathode, or vice versa.

FIG. 3 b is a top view of the electrode array 310 comprising electrodes31, 32, 33, 34, and 35; wire bundle 29; insulated wire segment 30; andinsulated wire ring 1003 of FIG. 3 a. The electrode 35, hidden in FIG. 3a is seen on FIG. 3 b. FIG. 3 c is a side perspective of the electrodearray 310 comprising electrodes 31, 32, 33, 34, and 35; wire bundle 29;insulated wire segment 30; and insulated wire ring 1003 of FIG. 3 a. Theneedles 36 are coupled to the electrodes 31, 32, 33, 34, and 35. Two ormore electrodes may simultaneously be used as anodes or cathodes forelectrical therapy. The electrodes 31, 32, 33, 34, and 35 comprise anelectrode array 310 that can be used to increase the effectiveness ofelectrical therapy by establishing an electric field pattern thatencompasses all of the tumor volume. In a preferred embodiment, thistype of electrode array 310 can be used for electrochemical therapyand/or electroporation.

Turning now to FIG. 4 a top view of an electrode array 311 is depicted.The electrode array 311 of FIG. 4 has been modified from the electrodearray 310 of FIG. 3 a-3 c by including four electrodes 32, 33, 34, and35 instead of five electrodes 31, 32, 33, 34, and 35 and coupling asingle needle 36 for fixation to a central non-electrical connection 37.Shown are a wire bundle 29; the electrodes 32, 33, 34, and 35; theneedle 36; the central non-electrical connection 37; and the insulatedwire ring 1003. The electrodes 32, 33, 34, and 35 are anchored to atissue via the needle 36, which is not directly associated with any oneof the electrodes 32, 33, 34, and 35. Needle 36 is mechanically coupledto the electrode array 311 via the central non-electrical connection 37but, as depicted, is electrically isolated from the electrodes 32, 33,34, and 35.

Illustrated in FIG. 5 a-5 b is an electrode array 312. The electrodearray 312 of FIG. 5 a-5 b has been modified from the electrode array ofFIG. 3 a-3 c 310 by utilizing a single needle 36 to anchor the electrodearray 312. Shown are the electrode array 312; a wire bundle 29; aninsulated wire segment 30; electrodes 31, 32, 33, 34, and 35; the needle36; and an insulated wire ring 1003. FIG. 5 a is a top view and FIG. 5 bis a side perspective view. In FIG. 5 a each of the electrodes 31, 32,33, 34, and 35 is coupled to the wire bundle 29 via the insulated wirering 1003. The electrodes 32, 33, 34, and 35 are coupled to theinsulated wire ring 1003, while the electrode 31 is coupledindependently to the wire bundle 29 via the insulated wire segment 30.Only the electrode 31 is mechanically coupled to the needle 36 as ananchoring means. The needle 36 may or may not serve as part of theelectrode 31. FIG. 5 b is a side perspective of FIG. 5 a.

Shown in FIG. 6 a-6 b is an electrode array 314. The electrode array 314of FIG. 6 a-6 b has been modified from the electrode array 310 of FIG. 3a-3 c by including four electrodes 32, 33, 34, and 35 instead of fiveand by removing all fixation needles. Shown are the electrode array 314;the wire bundle 29; the electrodes 32, 33, 34, and 35; and an insulatedwire ring 1003. FIG. 6 a is a top view and FIG. 6 b is a sideperspective view. In FIG. 6 a each of the electrodes 32, 33, 34, and 35is coupled to the wire bundle 29 via the insulated wire ring 1003. Noelectrode is coupled to a needle for fixation means. In this case, theelectrode array is placed on top of or around a tumor. In FIG. 6 b, theelectrodes 32, 33, 34, and 35 are shown coupled together via theinsulated wire ring 1003 to the wire bundle 29. No electrode is coupledto a needle for placement or anchoring means.

FIG. 7 a-7 b are illustrations of an electrode array 316. The electrodearray 316 of FIG. 7 a-7 b has been modified from the electrode array 310of FIG. 3 a-3 c by including four electrodes 32, 33, 34, and 35 insteadof five and by using an anchoring hook in lieu of a fixation needle orneedles. Shown are the electrode array 316; a wire bundle 29; electrodes32, 33, 34, and 35; an anchoring hook 38; and an insulated wire ring1003. FIG. 7 a is a top view and FIG. 7 b is a side perspective view. InFIG. 7 a each of the electrodes 32, 33, 34, and 35 is coupled to thewire bundle 29 via the insulated wire ring 1003. No electrode isdirectly coupled to a needle for fixation. Instead, an anchoring hook 38is coupled to the wire bundle 29; however, the anchoring hook 38 can beplaced at any place on the electrode array 316. The anchoring hook 38secures placement of the electrode array 316 by hooking into tissue. Inone variation, the anchoring hook 38 may be secured to healthy tissue toincrease stability. In FIG. 7 b the electrodes 32, 33, 34, and 35 areshown coupled together via insulated wire ring 1003 to wire bundle 29.The anchoring hook 38 is shown coupled to wire bundle 29.

In accordance with further variations, the anchoring hook 38 or severalanchoring hooks may be used either alone or in combination with afixation needle or needles.

Looking now at FIG. 8 a-8 b, a non-continuous electrode array 318 isdepicted. The non-continuous electrode array 318 of FIG. 8 a-8 b hasbeen modified from the electrode array 310 of FIG. 3 a-3 c by notattaching electrodes in a complete circle, i.e. by substituting theinsulated wire ring 1003 for a curved structure, or insulated wire “C”1005. Shown are the electrode array 318; a wire bundle 29; theelectrodes 32, 33, 34, and 35; fixation needles 36; and an insulatedwire “C” 1005. The electrodes 32, 33, 34, and 35 are coupled togethervia the insulated wire “C” 1005. The fixation needles 36 are coupled tothe electrodes 32, 33, 34, and 35. The needles 36 may or may not serveas part of the electrodes 32, 33, 34, and 35. The insulated wire may beflexible to allow any conformation of the insulated wire “C” 1005 andany relative position of the electrodes 32, 33, 34, and 35. For example,the electrodes 32, 33, 34, and 35 may be arranged in a partial circle orthree-quarter circle (or “C”), as shown, a straight line or a line witha bend, such as a 90° bend, or the like, a complex curve, or the like.The non-continuous electrode array 318 of FIG. 8 a-8 b may beadvantageously used when a tumor is awkwardly located or shaped, ordifficult to surround with a ring of electrodes for any other reason. Itis generally accepted that cancerous tumors should not be broken apartand, as such, a non-continuous electrode array 318 will allowflexibility in positioning.

Referring now to FIG. 9, an electrode array 39 with lead adapters 24 and1620 (such as shown above in FIG. 2 f) is shown in connection with atumor. Shown are a generator 1, a lead 2, a tumor 6, the lead adapters24 and 1620, and a multiple electrode array 39. The electrode array 39is electrically coupled to the generator 1. The multiple electrode array39 may be placed on top of, around, and/or adjacent to the tumor 6. Themultiple electrode array 39 may be anchored to the tumor 6 by anyfixation means such as a needle, hook, barbed hook, “corkscrew”, or anyother suitable suture for mechanically securing the multiple electrodearray 39 to the tumor 6 or to nearby tissue. Because the lead 2 and themultiple electrode array 39 together may be larger or bulkier than asingle electrode lead, tunneling the lead to the tumor 6 may beproblematic. To overcome this difficulty, the lead adapters 24 and 1620may be used. The lead adapters 24 and 1620 are located at both ends ofthe lead 2 with lead adapter 24 lying closest to the generator 1 and thelead adapter 1620 lying closest to the electrode array 39. In this way,the multiple electrode array 39 can be placed on or proximate to thetumor 6 and connected to the generator 1 by way of the lead 2, which canbe tunneled through tissue that may be interposed between a suitableimplantation site for the generator 1 and the tumor 6, where themultiple electrode array 39 must be located.

As will be appreciated by one of ordinary skill in the art, manyvariations of electrode arrays may be used in electrical therapy. Theexamples described herein are by way of example and in no way limit thescope of the invention. Any combination of the numerous optionsdescribed herein or otherwise suitable variations can be used to deliverelectrical therapy.

For example, a non-continuous ring of electrodes may be used with ananchoring hook. In addition, two electrode arrays may branch from thesame electrical connection on the generator 1 by way of, for example, alead adapter. Therefore, any of a virtually infinite number ofcombinations of options, configurations, and features described hereinare contemplated by the inventors.

Shown in FIG. 10 a-10 b is an example of an electrode arrangement thataccommodates electrical therapy and electroporation. Shown are a tumor6; electrodes 40, 41, and 42; a DC ablation current 43; and anelectroporation current 44. In this arrangement, three electrodes 40,41, and 42 are placed in and around the tumor 6. The electrodes 40 and42 lie at a periphery of the tumor 6 and the electrode 41 is placed at acenter of, on top of, or below the tumor 6. By utilizing threeelectrodes, both DC ablation and electroporation can be performed. In apreferred embodiment, DC ablation current 43 occurs between theelectrodes 40 and 42, as shown in FIG. 10 a, and electroporation occursbetween the electrodes 40 and 41, or between 41 and 42, as shown in FIG.10 b. Typically a set of electrode pairings having a greaterinterelectrode distance, such as between the electrodes 40 and 42, incomparison to electrodes 40 and 41, or 41 and 42, are used in electricaltherapy to create the maximum electric field for encompassing largeportions of a tumor, as shown in FIG. 10 a. However, any combination ofelectrodes may be used for electrical therapy. Shown in FIG. 10 b, twosets of electrode pairings with a smaller interelectrode distance may beoptimally used for electroporation in order to increase the electricfield intensity for a given pulse voltage amplitude. In a preferredembodiment, a chemotherapeutic agent may enter the electroporated areafaster than cells in the surrounding area. The area between electrodes40 and 41 and/or 41 and 42 will preferably consist of a large portion ofthe primary tumor whereas the area between the electrodes 40 and 42might include metastases as well as the border of the primary tumor.

A three-axis electrode system 350 is shown in FIG. 11 and comprises aconfiguration of three leads 45, 46, and 47; multiple electrodes 48; andthe three-axis system 350 for electrical therapy. The three-axis system350 is electrically coupled to an internal and/or external power source(not shown). Each of the three leads 45, 46, and 47, which have aplurality of spaced apart electrodes 48 along a portion of their distalends are implanted into a tumor 6 orthogonally and intersect near thecenter of the tumor 6. As the size, shape, density, and othercharacteristics of the tumor 6 change during application of electricaltherapy, the central vector of current flow can be altered throughselectively activating multiple electrodes 48 on the x, y, and zcoordinates. In this way, the system can target the center of thetumor's mass. Additionally the system can selectively designateelectrodes 48 as anodes or cathodes, or both anodes and cathodes in anysequence (such as using the hex bridge 300, such as shown in FIG. 2 e-2f) and alter the 3-dimensional distribution of currents. The system canalso pulse for more energy efficiency, such as by delivering one or morepulses of current between one or more pairs (or more) of the electrodes48. In some cases it is more energy efficient to pulse at a low dutycycle than to maintain a steady current, even when the pulses may be ata higher voltage.

Turning now to FIG. 12 a-12 b leads 49, 50, 51, and 52 with uniqueidentification marks 53, 54, 55, and 56 are illustrated. Shown are fourleads 49, 50, 51, and 52; the unique markings 53, 54, 55, and 56; and atumor 6. The leads 49, 50, 51, and 52 are electrically coupled to aninternal and/or external power source (not shown). The leads 49, 50, 51,and 52 are coupled with any number and configuration of electrodes (notshown).

Each lead 49, 50, 51, and 52 is shown with its unique marking 53, 54,55, and 56 respectively. The unique marking 53, 54, 55, and 56 isindividually identifiable under imaging. The unique marking may be of adifferent material distinguishable from the lead material under imaging.By visually tracking the tumor 6 in relation to the leads 49, 50, 51,and 52, via their unique markings 53, 54, 55, and 56, during treatment,therapy can be reprogrammed, such as through transcutaneous telemetry,to deliver electrical therapy tailored to any changes in the tumor 6.For example, the leads and/or electrodes (not shown) may be shifted overtime as the size, shape, or position of the tumor 6 changes. Referringto FIG. 12 a, a set of four uniquely marked leads 49, 50, 51, and 52surround the tumor 6. Then, in FIG. 12 b, the same tumor 6 has changedsize, shape, and position. In this case, based on the unique markings53, 54, 55, and 56 of the leads 49, 50, 51, and 52, the leads 49, 50,51, and 52 and/or electrodes (not shown) may be appropriatelyrepositioned to target the center of the altered tumor. The markings maybe a different number of stripes near the tip of each lead, such asshown in FIG. 12 a-12 b. However, any other type of unique marking thatdistinguishes one lead from another in the local tumor area may be used.

In another embodiment, imaging may also be accomplished by magneticresonance imaging (MRI), computed tomography scan (CT), and ultrasound(echo imaging). The leads of the device may be adapted to withstand theradiation associated with MRI imaging by the addition of shunting andopening protection circuitry to prevent the induction of high currentsthrough Faraday's law acting on the current loop of the electrodes.Alternatively, current loops may be generated from one wire and a returnpath through the tissue.

To enhance MRI and CT scanning, a contrast agent may be administereddirectly into the core of the tumor to be scanned. Alternatively,depending on the desired outcome of the MRI or CT scan, the contrastagent may be administered to the periphery of the tumor (i.e. in thevicinity of the tumor). The contrast agent may be injected with a needleor syringe, or it may be administered via any of the internal reservoirsand drug pumps described hereinbelow. The contrast agents may be forexample, iodine compounds and solutions and charged micro spheres. Microspheres are particularly advantageous in ultrasound imaging.

In another embodiment, the electrical therapy system may enhance imagingby applying current to increase the concentration of certain chemicals,such as oxygen. Oxygen concentration may be increased by forcing allelectrodes anodal and/or by administering certain oxygenatingsubstances, such as perfluorocarbons and/or any other oxygenators, suchas, for example, any of the oxygenating substances describedhereinbelow. Using this technique, the imaging device can read currentdistributions by back calculations from the oxygen and hydrogenconcentrations, thereby rendering the tumor more visible.

Referring now to FIG. 13 a-13 e various types of lead anchoringmechanisms are illustrated. Shown are a tumor 6, a screw-in lead 57, ascrew 58, pronged lead 59, two or more prongs 60, a telescoping lead360, telescoping cylindrical electrode section 61, stationary electrodesection 62, adjustable screw-in lead 1111, adjustable screw-in electrode1113, adjusting means 1115, and rotatable coupling means 1117. Each ofthe leads 57, 59, 360, and 1111 is coupled to an internal and/orexternal power source (not shown).

FIG. 13 a shows the screw in lead 57. Adapted with the screw 58, thescrew-in lead 57 is designed to be left within a tumor 6 during therapy.Shown in FIG. 13 b is the pronged lead 59 ending with two or more prongs60, which are expanded into the tumor 6 during implantation and are leftexpanded throughout therapy. Depicted in FIG. 13 c, is the telescopinglead 360. Shown are the telescoping lead 360 and one or more overlappingtelescoping cylindrical electrode sections 61 and stationary electrodesection 62, the telescoping cylindrical electrode section 61 has beenextended from the stationary electrode section 62. The telescopingcylindrical electrode section 61 may be adjusted either pre- orpost-implantation to an optimum length in order to anchor to the tumor 6and create electrical contact therewith.

FIG. 13 d depicts an adjustable screw-in lead 1111. The adjustablescrew-in lead 1111 may be repositioned during electrical therapy asneeded to “chase” a tumor. The adjustable screw-in lead 1111 is coupledat one end to a power source (not shown) such that the power sourcedelivers electrical therapy to the adjustable screw-in lead 1111. At theother end, the adjustable screw-in lead 1111 is coupled with a rotatablecoupling means 1117. The rotatable coupling means 1117 is electricallyand mechanically coupled to an adjustable screw-in electrode 1113 suchthat the electrical therapy delivered by the power source (not shown),and carried by the adjustable screw-in lead 1111, is delivered to thescrew-in electrode 1113 via the rotatable coupling means 1117. Rotatablecoupling means 1117 may be, in one embodiment, a washer. The adjustablescrew-in electrode 1113 may be in various sizes and lengths depending onthe tumor characteristics (e.g. size, location, density, andcomposition). In a preferred embodiment, the adjustable fixation screwmay be in the range of 0.2 to 2 inches in length and 0.1 to 1 inch indiameter. Coupled to the top of the adjustable screw-in electrode 1113is an adjusting means 1115. Adjusting means 1115 allows the adjustablescrew-in electrode 1113 to be easily inserted and removed from a tumor.Additionally, the adjusting means 1115 allows for easy repositioningduring electrical therapy. Adjusting means 1115 may be designed with anelevated curve as shown. Alternatively, adjusting means 1115 may beshaped like a screw head or a bolt head. FIG. 13 e is a top view of theadjusting means 1115.

Shown in FIG. 14 is a means for directly anchoring a lead to healthytissue. Illustrated are a tumor 6, a lead 63, a fixation means 64, andhealthy tissue 65. The lead 63 is coupled to an internal and/or externalpower source. The lead 63 may be coupled with any number andconfiguration of electrodes (not shown).

The lead 63 is shown inserted into the tumor 6. The lead 63 is held inposition by means of a fixation device 64, which is directly anchoredinto the healthy tissue 65, which is peripheral to the tumor 6. Becausetumor tissue may be soft and/or watery, a means for fixing a lead tonearby healthy, solid tissue, as shown, may be advantageous. In thiscase, the lead 63 remains fixed in place with no regard to anycharacteristics of the tumor 6. Additionally, as electrical therapy isapplied, the tumor 6 may change size, shape, and density, thus anchoringthe lead to healthy tissue may render readjusting the lead unnecessary.Fixation means may be a hook, needle, prongs, screw and any other devicecapable of anchoring a lead to healthy peripheral tissue.

Turning now to FIG. 15 a means for indirectly anchoring a lead tohealthy tissue is illustrated. Shown are a tumor 6, a lead 63, healthytissue 65, a suture 66, and a suture sleeve 67. The lead 63 is coupledwith an internal and/or external source of power (not shown). The lead63 may be coupled with any number and configuration of electrodes.

The lead 63 is shown inserted into a tumor 6. The lead 63 is held inposition by means of the suture 66 in the suture sleeve 67. The suture66 indirectly anchors the lead 63 into healthy tissue 65 peripheral tothe tumor 6. Again, because tumor tissue may be soft and/or watery, ameans for fixing a lead, either directly or indirectly, to nearbyhealthy solid tissue may be advantageous. In this case, despite anychanges in size or composition occurring in the tumor 6, the lead 63remains fixed in place. The lead 63 will remain in place regardless ofchanges occurring within the tumor 6.

The above illustrates only a few of the types of anchoring mechanismspossible for anchoring a lead to a tumor. The anchoring mechanisms maybe of numerous shapes and sizes. Ideally, the anchoring mechanism isselected relative to the size, density, and location of the tumor ineach circumstance. Importantly, tumor tissue, such as the tissue towhich a lead of the present embodiment is anchored proximately, is quitedifferent from heart muscle to which a pacemaker is anchored. Tumortissue tends to be soft and retracting and, therefore, the anchoringdevice should permit penetration of this type of cancerous tissue whileallowing safe removal. Anchoring leads of the present embodiment areakin to active fixation pacing leads rather than passive fixation leads.The anchoring mechanism may or may not also act as one or more of theelectrodes. For example, in one embodiment, the anchoring means maydouble as the electrodes; both anode and cathode configurations arecontemplated. Alternatively, the anchoring mechanism may not serve as anelectrode, in which case the electrode may be at the end of the leaddistal to the anchoring mechanism.

The lead depicted in FIG. 16 has additional features and options thatmay be advantageous in certain circumstances. Shown are lead 68, anon-stick coating 69, a lumen 70, and an inflatable balloon 71. The lead68 is coupled to an internal and/or external source of power (notshown). The lead 68 may be coupled with any number and configuration ofelectrodes (not shown).

The lead 68 of FIG. 16 features the non-stick coating 69 on an externalsurface of the lead 68. Additionally, the lumen 70 runs lengthwise alonga distance of the lead 68. The inflatable balloon 71 is coupled to adistal end of the lead 68. The lumen 70, running the entire length ofthe lead 68, is useful for insertion, extraction, gas removal, andliquid removal. Because metabolic changes in a tumor may cause gas andliquid production, the lead 68, comprising the lumen 70 configured toremove both gases and liquids may be advantageous. During periods ofhigh current injection, when gas and liquid production are likely to begreatest, gas and liquid removal may be particularly advantageousbecause excess gas and/or excess liquid may interfere with electricaltherapy and/or cause bloating and/or pain.

In another embodiment, the lumen 70 may be completely open from end toend for a so-called “over the wire” insertion technique. Alternatively,the lumen 70 may be partially closed at a distal end, opposite theinflatable balloon 71, to block a stylet. The non-stick coating 69,which is applied to the outer surface of the lead 68, renders insertionand removal of the lead 68 easier. The inflatable balloon 71 isoptionally coupled with the distal end of the lead 68 for securing thedistal end of the lead 68 in a tumor. Additionally, the inflatableballoon 71 may be conductive such that by controlling the radius(through inflation or deflation) current density can also be regulated.Holes of any number, but preferentially two, may be associated with thedistal end of the lumen 68 comprising the inflatable balloon 71 to allowfor gas and liquid removal. However, the holes should be small enough toprevent a stylet from escaping. Any of the variations described hereinmay be used singly, together, or in any combination.

Referring to FIG. 17-18 additional features and options that may beadvantageous in various circumstances are depicted. Shown featuresinclude optical fibers 72, temperature sensors 73, electrodes 74, andleads 375 and 377. The leads 375 and 377 are coupled to an internaland/or external source of power. Furthermore, the leads 375 and 377 maybe coupled with any number and configuration of electrodes.

FIG. 17 shows a distal end of a lead 375 comprising the ends of each oftwo optical fibers 72 and two temperature sensors 73. The optical fibers72 allow for visualization under acute imaging. Acute imaging can beaccomplished indirectly by using a Charge Coupled Device (CCD) inside agenerator (not shown, but such as in FIG. 1) for imaging tumorregression or chemical sensing. For example, the absorption ortransmission of various infrared light frequencies by blood is stronglyinfluenced by a level of oxygen saturation. Therefore, optical fibers 72may be useful for monitoring oxygen levels, by delivering light throughone fiber and then monitoring the transmitted light through the otherfiber. Temperature sensors 73 are also coupled to the end of a lead toallow monitoring of the temperature in and around a tumor. Temperaturesensors 73 may be of any variety such as thermistor and thermocoupletemperature sensors. As tumors tend to have an elevated temperature incomparison to healthy body tissues, the progression or regression of atumor can be monitored by monitoring variations in temperature at ornear the electrodes over time (excluding localized heating that maybriefly accompany electrical therapy). In another embodiment, thetemperature sensors 73 may be placed on the sides of the lead or acatheter such as shown in FIG. 18. Shown in FIG. 18, temperature sensors73 are placed along lead 377 to allow for temperature monitoring atvarious positions within the tumor.

In another embodiment, the tip electrodes and one or more ringelectrodes on the lead and/or the catheter may be roughened by, forexample, sandblasting, chemical surface modulation, physical surfacemodulation, or any other means of modification in order to produce ahigh microscopic surface area to minimize polarization and corrosion.

Depicted in FIG. 19 a-19 c is a dielectric sensor 1200 for measuringcapacitance and resistance. Shown are two leads 75 and 379, a spacer 76,a fixed distance 77, spherical electrodes 78 and 381, cylindricalelectrodes 1202 and 1204, and a tumor 6. The leads 75 and 379 arecoupled to an internal and/or external source of power (not shown).

Turning to FIG. 19 a, leads 75 and 379 are coupled to sphericalelectrodes 78 and 381, which are held at the fixed distance 77 by thespacer 76. The spacer 76 holds the electrodes 78 and 381 at the fixeddistance 77 ensuring that the electrodes do not migrate during thecourse of therapy. The resulting non-migrating or rigid structure shouldcover a maximum area of the tumor 6. In this arrangement, the electrodes78 and 381 are used to deliver electrical therapy to tumor 6, but mayalso serve as a capacitor with the tumor as a dielectric, allowing forthe measurement of the capacitance and resistance of the tumor 6. Thesevalues can be used to measure necrosis, tumor size, tumor density, andother characteristics.

Shown in FIG. 19 b-19 c, leads 75 and 379 are coupled to cylindricalelectrodes 1202 and 1204. Leads 75 and 379 are coupled at one end to apower source (not shown) such that the leads 75 and 379 may deliverelectrical therapy to cylindrical electrodes 1202 and 1204. Cylindricalelectrodes 1202 and 1204 are designed to “cup” or surround the tumor 6in order to measure capacitance and resistance of the tumor 6 and/ordeliver electrical therapy. FIG. 19 c is a cross-sectional view of FIG.19 b.

Because tumors vary in both shape and size, or may change shape and sizeduring the process of electrical therapy, it is envisioned thatdifferent sizes and shapes of electrodes, such as the sphericalelectrodes 78 and 381 (as shown in FIG. 19 a) and the cylindricalelectrodes 1202 and 1204 (as shown in FIG. 19 b-19 c), may be used tomaximize tumor surface area exposed to the electrical field.Additionally, because tumors may vary in size, it is envisioned that thespacer 76 may be adjusted appropriately to accommodate a tumor of anysize.

Represented in FIG. 20-21 is a method and device for creating a conduitfor leads to pass through tissue to a tumor. Shown are a generator 1, atumor 6, a tunnel 79, a conduit 80, surrounding tissue 81, and leads 82.The leads 82 are coupled to generator 1.

A trocar or other surgical tool is used to create the tunnel 79 throughsurrounding tissue 81. The conduit 80 is then passed through the tunnel79. Looking to FIG. 21, the leads 82 attached at proximal ends to thegenerator 1 can be easily fed through the conduit 80 to the tumor 6.Following therapy, the leads 82 can be easily extracted through theconduit 80. The conduit 80 can be made of various materials includinginert and/or non-reactive metals, such as platinum and stainless steel.In a preferred embodiment, the conduit 80 is made of absorbable materialwhich the body can safely dissolve over time. In the case ofnon-absorbable conduits, the conduit 80 should be removed from apatient's body when the leads 82 are removed.

The leads contemplated in variations of the present embodiment may becoupled either permanently or detachably to a generator or other powersource (internal and/or external). Each particular situation willdetermine the need for a permanently coupled system versus a detachablycoupled system. For example, depending on the desired cost versus systemflexibility, a permanent or detachable system may be desired. A low costsystem could employ leads of fixed length and optionally means foranchoring the leads to the tissue. In the low cost system, the leads arepermanently attached to the generator.

The leads and the electrodes of the device may be comprised of platinumor other noble metal, and alloys thereof. For example, the electrodes ofthe present embodiment may be made of a few strands of platinum iridiumcoated with insulation. Furthermore, the leads and the electrodes of thepresent embodiment may be formed of high-strength, non-reactive metals,such as titanium and stainless steel. The leads and the electrodes madeof conductive oxides and semiconductors can also be used. Additionally,any metal used in implantable pacemakers may also be used in the deviceof the present embodiment. Unlike pacemakers, however, there willgenerally be no need for sophisticated non-polarizable electrodes in thedevice of the present embodiment.

Determining the type of material which a lead should be made of may becase specific. A material's expense, strength, and flexibility should beconsidered. Depending on the severity of a case and location of a tumor,strength and flexibility of a material may make one type of metal abetter choice than another. For example, the major stress placed on thelead is generally during implantation, in which case the lead's strengthshould be a compromise between reducing the diameter and being able towithstand kinking during implant. Alternatively, a tumor located in anactive part of the body, such as a sarcoma in the arm or leg, mayexperience more stress after implantation, in which case a lead with alarger diameter or a material of greater strength should be used.

The leads of the present embodiment may be supplied in various lengthsor in a single length, with excess lead being wrapped around thegenerator housing.

A lumen or stylet aperture is optional.

3. GENERATOR

Looking now at FIG. 22 a block diagram of a basic generator 1 of thepresent embodiment is depicted. Shown are the generator 1, a tumor 6, apower source 83, a controller 84, a driver 85, and lead electrodes 86.

In the generator 1 of FIG. 22, the power source 83 is coupled to thecontroller 84 which is coupled to the driver 85. In turn, the driver 85is coupled to the lead electrodes 86. The power source 83 may be aprimary battery, a rechargeable battery, or a receiver of radiofrequency (RF) or inductive energy coupled from outside the body.

In a preferred embodiment, battery voltage is available to the driver85, which provides electrical therapy to the lead electrodes 86. In apreferred embodiment, direct current is provided to the lead electrodes86. The controller 84 permits the voltage/current/coulombs to be turnedon or off and may consist of a magnetic reed switch activated by anexternal permanent magnet. The driver circuit 85 delivers regulatedvoltage or constant current to the electrodes 86 to compensate forchanges in impedance seen at the electrodes 86. Alternatively,electrical therapy may be delivered to a patient via total amount ofcoulombs, in which case resistance and impedance do not affect theamount of electrical therapy delivered.

Shown in FIG. 23 is a block diagram of an enhanced generator 1 of thepresent embodiment in which many parameters can be programmed, such asvoltage amplitude, current amplitude, output polarity (to switch anodesand cathodes), and total number of coulombs to be delivered to theelectrodes. The generator 1 of FIG. 23 comprises a transducer 87, acontroller 88, an external instrument 89, a telemetry circuit 90,electrodes 91, a sensor processor 92, a warning signal 93, amicroprocessor 94, and a driver 95. Commands may be transmitted by theexternal instrument 89 to the transducer 87 and the controller 88. Thetelemetry circuit 90 permits data to be transmitted to the externalinstrument 89. Perceived data may include battery life remaining,coulombs delivered, and sensory information from a tumor 6, such astumor size, density, or chemistry data (e.g. pH). Other embodimentsinclude pressure measurements as the tumor 6 shrinks or grows, an indexof tumor regression or proliferation, and an electrode displacementindication. This type of information can be detected by the electrodes91 and specialized sensors such as physical, impedance, pressure,optical, and chemical sensors. Sensors can be designed to tolerateradiation ionization if radiation therapy is probable. Sensedinformation is processed at the sensor processor 92 and can betelemetered by the telemetry circuit 90 to the external instrument 89via the transducer 87 and may be used to control the generator 1directly. For example, sensing of excessive heating or gas buildup cancause the therapy to be halted until the tissue cools or the gas isreabsorbed. Other features of the generator may include defibrillationprotection, the controller 88 gradually increases voltage at the startof the treatment, a programmable timer to control duration of therapyand sequence of therapy, and the warning signal 93, which can be audibleor vibration, to the patient to signal battery depletion, an open orshort circuit, and other conditions warranting attention. The entiredevice is preferably under control of the microprocessor 94, althoughits simplicity may not require computer control. The driver 95 may haveseveral sections, each suitable for a different therapy depending on thevoltage and current levels required. Preferably, the driver includes thehex driver of FIG. 2 e-2 f. Portions of the entire device may beoperated in a “sleep” mode to conserve energy when not in use.

The sensor processor 92 is preferably a direct current amplifier whichdetects intrinsic body currents. The generator 1 can begin the therapyprocess by “priming the pump” with a short duration direct current whichhelps the body initiate its own therapeutic currents. Output currentlevels may be either programmed or adjusted automatically to optimumlevels to minimize tumor cell proliferation.

In another embodiment, the external instrument 89 may communicate withthe implanted electrical therapy device. Among the many advantages ofthis particular conformation, this variation will allow for testing ofthe implanted leads prior to unsealing the sterile implantable devicefrom its packaging. The sterile electrical therapy device may have shortelectrode jumpers extending out from the connection head to allow fortemporary connections (in application, the leads are inserted into ornear to tumors during surgery). The outside box holding the implantabledevice may be “jumped” to previously implanted electrodes. A programmermay then communicate with the unopened (sterile) device in order toverify appropriate positioning of the electrode leads 91.

The programmer may also display various data including the waveforms ofimpedance, voltage/current/coulombs, and pH in and around the tumor(s),which may be downloaded into the programmer from the implantable device.These data or “oncogram” information are valuable in tracking thepatient's prognosis. For example, voltage and current are correlatedwith malignant activity, impedance and pH are related to the progressionor regression of malignancies, and the impedance spectrum (i.e. theZ(f)) which is the impedance across the tumor at various frequencies,will allows estimation of tumor size.

Various parameters, such as, for example, impedance, voltage/current,pH, oxygen, and temperature may be stored long term using analog todigital conversion and compression. Alternatively, the device may use adelta modulation scheme or store voltages/current directly onto a chargestorage device such as a capacitor array or one or more gates ofcomplementary metal oxide semiconductor devices.

Waveform morphology may be controlled by one or more parameters enteredinto the programmer thereby allowing storage of the exact desired waveshape that may be advantageously used until the patient's next clinicalexam.

The programmer may also administer and control instantaneous voltagesand currents for testing and shorter-term therapy. For example, it maybe desirable to deliver the first hour of therapy such that extreme pHchanges are accomplished (this may be done for example at a clinic).Because extreme pH changes are generally associated with higher levelsof electrical therapy, this step may be advantageously accomplished viaan external power source thereby reducing current drain on the implanteddevice battery. Furthermore, early monitoring of the tumor response maybe available because the initial therapy may take place in a clinic (orother medical facility).

Furthermore, the programmer may also accept data from other sources. Forexample, an MRI or CT scan may locate a tumor and approximate size (asdescribed hereinabove) and input the data to the programmer. Byinputting such information, the programmer may select or recommendvarious parameters such as waveform, voltage, current, and timedurations to optimize electrical therapy. The programmer may send asimplified outline of the tumor and electrode positions to the implanteddevice for storage. The stored information and images may then bereferred to as a reference point.

The programmer may be based on any of a personal digital assistant(PDA), tabletop computer, and laptop computer. Communication between theprogrammer and the device may be via, for example, RF, magnetic wirelesstelemetry, and/or any other of the communication methods describedherein. The implantable device may store many parameters in addition to“oncograms” such as, battery internal resistance, unloaded and loadedvoltages, output therapeutic currents, therapeutic voltages, storedtherapeutic waveforms, and data obtained from additional analyte sensorssupported by the implanted device.

The programmer may send commands to change waveform morphology, enableand disable the programming functions, and interrupt or tune the closedloop control (as described hereinbelow). Additionally, the programmermay enable a sensor driven open loop function (the transfer function maybe linear or non-linear).

In another embodiment, the programmer may download whole waveformdescriptors. The descriptors may be abbreviated mathematical descriptorsor continuous analog-like descriptors such as an MIDI file or an MP3file.

The device of FIG. 23 may be controlled by a magnet or a patientnotification device. The magnet may be used by a patient or health carepractitioner to turn off therapy or to provide other controlling signalsto the implantable device by placing the magnet in the proximity of theimplanted device. This procedure may be performed if a patient feelsthat the therapy is too painful, is concerned for other reasons, or isproviding some additional control inputs to the implanted device.

The patient controller can be used by the patient with very simplecommands to make modifications to therapy. Patients can increase thecurrent of the therapy. Alternatively, if the increased current iscausing too much pain then the patient can reduce the currenttemporarily until the next follow up visit. Further, the patient canincrease the level of TENS (transcutaneous electrical nerve stimulation)to optimize the blocking of pain. This TENS stimulation is generated bythe implanted device. Also, the patient can increase the level of druginfusion (as described hereinbelow).

The patient can also command the device to go into a nocturnal mode.While in nocturnal mode the device will deliver high current therapyonly during the night when the patient is less likely to be sensitive tointernal pain. Alternatively, the patient may request a circadian rhythmapproach. During a circadian rhythm cycle critical high-currenttherapies are administered during the best times of day for thepatient's type of cancer. This method is advantageous because, as knownby those of ordinary skill in the art, different types of cancer respondto chemotherapeutic agents much better at different times of day. Otheroptions include a push button indicating the presence or absence of painand a number correlating to the pain level. Additionally, the patientmay have access to a medication button showing when medications and/ormeals were taken. These data may be stored in the implanted device orthe external patient control unit for later downloading.

The device may also generate an audible or electrical stimulationreminding the patient to take their medications and to eat. The devicemay also generate a warning signal (audible or electrical stimulation)if the patient does not take their medication or meals within a certaintime frame.

Low battery condition may also alert the patient with an appropriatetone. This tone signifies to the patient that they must go into theclinic to have the device recharged or replaced depending upon themodel. The patient control unit may communicate to the device to verifythat the device is on to reassure the patient. The patient can also bealerted to lead breakage or other electrode contact problems so thathe/she can return to the clinic to have the problem checked.

The system may alert the patient through a device signal and/or throughthe patient control that the appropriate therapeutic goal has beenachieved. This signal may signify that a certain pH has been attainedfor a given length of time or that by sensed oxygen level and/ortemperature level that the tumor appears to have shrunk significantly.These conditions may indicate to the patient that they should return totheir clinic for a follow-up exam.

Shown in FIG. 24 is a generator comprising a port. Shown are a port 96,leads 97, drive circuits 98, and a generator 1. The port 96 is builtinto the generator 1 electrically between the drive circuits 98 and theleads 97. The port 96 can accept electrical input from a source otherthan the generator 1. In a preferred embodiment, the electrical sourceis located outside the body. The location of the port 96, between thedrive circuits 98 and the leads 97, allows electrical input from asource other than the generator 1 to be directly connected to the leads97. The port 96, positioned as such is useful to modify electricaltherapy as needed from an outside source. Modified electrical therapymay be in the form of electroporation therapy with or without additionalchemotherapy, specialized electrical therapy regimens, and electricalprograms otherwise altered from an internal system.

Illustrated in FIG. 25 is an example of a port for use in electricaltherapy. Shown are a port 99, a conducting needle 100, a self-sealingdiaphragm 101, skin 102, a tumor 6, leads 103, and electrodes 104. Theport 99 is implanted below the skin layer 102. The port 99 is coupled tothe leads 103. At the distal end of leads 103, opposite the port 99, arethe electrodes 104. The electrodes 104 are positioned in or around thetumor 6. The conducting needle 100 can be inserted into the port 99through the self-sealing diaphragm 101 to make an electrical connectionto the leads 103. The self-sealing diaphragm 101 can be made of any typeof material useful for excluding body fluid. In a preferred embodimentthe self-sealing diaphragm is made of silicone. In another preferredembodiment, the conducting needle 100 is coupled to an externalelectrical source such as an external generator (not shown). In thisway, the external generator can make a direct electrical connection tothe leads 103 and the electrode 104 via port 99. However, the leads 103may additionally be coupled to an internal power source (not shown). Theconducting needle 100 can be any useful for cleanly penetratingself-sealing diaphragm 101. In a preferred embodiment, a Huber pointneedle may be used.

The port 99 can be used in electrical therapy systems with or without animplanted generator and with or without an external electrical source.For example, means of powering an electrical therapy system of thepreferred embodiment may comprise an implanted system which is poweredsolely by an external source when coupled to the internal electricaltherapy system counterpart; the external power source may be coupled tothe internal counterpart by a port as described in FIG. 25 or any othermeans useful for powering the internal electrical therapy system.Alternatively, the electrical therapy system of the preferred embodimentmay be powered by an internal electrical source until such time anexternal power source is coupled to the internal electrical therapysystem in such a way to bypass the internal power source, such a port asdescribed in FIG. 25. The previous examples are for illustrationpurposes only and are in no way limiting to the numerous ways anexternal power source may be coupled to an internal electrical therapysystem.

Turning now to FIG. 26 an up close diagram of a conducting needle 106inserted into a port 109 is depicted. Shown are a diaphragm 105, aconducting needle 106, a needle stop 107, lead ends 108, and a port 109.The conducting needle 106 is shown inserted into the port 109. Theneedle stop 107 prevents the conducting needle 106 from puncturing thebottom of the port 109. Additionally, the needle stop 107 may serve as apositioning guide for correctly inserting the conducting needle 106 intothe port 109. As inserted into the port 109, the conducting needle 106completes an electrical circuit between an electrical source and theleads 108 which are connected to the electrodes. The electrical sourcemay be an implanted generator or external generator. In a preferredembodiment, the electrical source is an external generator. Needlecontact may be electrically checked by measuring impedance betweenelectrodes or of a resistor temporarily placed across the output. It isenvisioned that by including a port, short in-patient sessions ofelectroporation and/or high current/voltage DC ablation may be providedby an outside electrical source while consistent or long term electricaltherapy may be achieved by an implanted electrical source.Advantageously, by eliminating electroporation generating means from aninternal generator, need for high voltage generation circuitry and highpower supply is reduced; thereby reducing the cost and size of thedevice. According to this embodiment, electroporation may be used withor without chemotherapy. However, both electroporation and electricaltherapy could be provided internally as well as externally from the sameelectrical source.

4. METHOD OF THE PREFERRED EMBODIMENTS

Referring now to FIG. 27 a-27 f, methods of the preferred embodiment aredepicted. FIG. 27 a relates to an electrical therapy regimen for usewith a basic unipolar configuration of the preferred embodiment. FIG. 27b relates to an electrical therapy regimen for use with a bipolarconfiguration of the preferred embodiment. FIG. 27 c relates to anelectrical therapy regimen for use with chemotherapeutic agents. FIG. 27d relates to an electrical therapy regimen for use with radiationtherapy. FIG. 27 e relates to an electrical therapy method usingcoulombs. FIG. 27 f is an electrical therapy method using current.

Looking now to a basic unipolar configuration of the preferredembodiment depicted in FIG. 27 a, a method of the preferred embodimentis depicted. Beginning at step 109 a lead with at least one electrode isimplanted into, nearby, or adjacent to a tumor. In a preferredembodiment, the electrode is anodal and is implanted into a tumor andthe generator housing serves as a cathode.

At step 110 a generator is implanted away from the tumor. Determinationof the implantation site for a generator is dependent on a number offactors. For example, a generator may be implanted directly on a tumorwithout any leads. However, in some cases, such as when electricaltherapy is used in conjunction with radiotherapy, this option may not bedesirable because the device may be damaged by ionizing radiation(although in another embodiment the device may be protected withradiation shielding). Moreover, implanting a generator remotely may besafer for the patient and surgically more convenient. For example, inthe case of a brain tumor, it may not be feasible or desirable toimplant a generator in the head whereas the shoulder area may be moreappropriate. Although the inventors contemplate a generator implanteddirectly at the tumor site, in practice the generator is often implantedseveral cm away. In a preferred embodiment, the generator is implanted10 cm away; however, distances from 0 to 40 cm are acceptable. At step111 the generator is programmed by telemetry. Many parameters can beprogrammed such as duration of therapy, duty cycle, pulse width,voltage, current, total coulombs delivered, anode/cathode switching, andthe like. The specific parameters described below are only one sequenceof an infinite number of settings, and therefore, should be seen asillustrative only and in no way limiting.

In this example, directed to a basic unipolar configuration of thepreferred embodiment, at step 112 5-10 V are delivered between the leadelectrode and generator housing for 0.5 to 2 hours. In a preferredembodiment, the lead electrode is anodal while the generator housingserves as the cathode. However, in another embodiment, the leadelectrode may serve as a cathode while the generator housing serves asan anode. Moreover, the polarities of the lead electrode and generatorhousing may be designed to switch as desired during therapy.

Step 112 changes the pH in the tumor and begins rapid destruction. pHchanges down to about 2 and up to about 13 may be found at the anode andthe cathode, respectively. The pH change will be less at the housingsince the current density there is significantly lower relative to itslarge surface area. A change in pH of at least 2 may begin destruction.In a preferred embodiment, voltages in the range of 3 to 25 V anddurations in the range of 10 minutes to 2 hours are useful for changingthe internal tumor pH.

At step 113 the generator may optionally begin monitoring voltagebetween the anode and the pulse generator housing. If an internalintrinsic healing current is detected or a rest period is desired forany other reason, no further therapy is provided until the device isreprogrammed. As result, the system remains in idle mode at step 114.Alternatively, the device may automatically restart electrical therapyafter a preset amount of time. In a preferred embodiment, the systemremains in idle mode for 12 to 72 hours. The use of a rest period is setthrough the programmer at the judgment of the health practitioner.

However, if no internal healing current is detected or a rest period isnot desired for any other reason, therapy will immediately enter step115 where 50 mV to 1 V is delivered for 4-48 hours between the leadelectrode and the generator housing. This low voltage field applied atstep 115 may attract leukocytes (white blood cells) to the tumor inorder to clean up destroyed cells caused by step 112. A voltage of 50 mVis typically high enough to attract leukocytes, but below theelectrolysis level. In a preferred embodiment, voltages ranging from 50mV to 1 V and durations ranging from 4 to 48 hours are useful forattracting leukocytes.

Referring now to FIG. 27 b, another method of the preferred embodimentis shown. The method of FIG. 27 b represents a bipolar configuration ofthe preferred embodiment. Beginning at step 116 one or more leadscontaining at least one anode electrode and at least one cathodeelectrode are implanted into, nearby, or adjacent to a tumor. The leador leads and bipolar electrodes comprised therein may be of anyconfiguration.

At step 117 a generator is implanted away from the tumor. In a preferredembodiment, the generator is implanted several cm away with a preferreddistance of 10 cm while distances of 0 to 40 cm are acceptable. At step118 the generator is programmed by telemetry. Many parameters can beprogrammed such as duration of therapy, duty cycle, pulse width,voltage, current, total coulombs delivered, anode/cathode switching, andthe like. The specific parameters described below are only one sequenceof an infinite number of settings, and therefore, should be seen asillustrative only and are in no way limiting.

In this example, directed to a bipolar configuration of the preferredembodiment, at step 119 5-10 V are delivered between any combination andconfiguration of anode electrode or electrodes and any combination andconfiguration of cathode electrode or electrodes for 0.5 to 2 hours.This step 119 changes the pH in the tumor and begins rapid destruction.pH changes down to about 2 and up to about 13 may be found at the anodeand cathode, respectively. A change in pH of at least 2 may begindestruction. In a preferred embodiment, voltages in the range of 3 to 25V and durations in the range of 10 minutes to 2 hours are useful forchanging the internal tumor pH.

At step 120 the polarities of anode electrodes and cathode electrodesmay switch as desired during therapy. Polarities may advantageouslyswitch because tumors may respond differently to one polarity versus theother (e.g. anodic versus cathodic). A sensor or imaging may determinethe level of shrinkage which will positively correspond to the efficacyof treatment.

At step 121 the generator may optionally begin monitoring voltagebetween the anode and the pulse generator housing. If an internalintrinsic healing current is detected or a rest period is desired forany other reason, no further therapy is provided until the device isreprogrammed. As a result, the system remains in idle mode at step 122.Alternatively, the device may automatically restart electrical therapyafter a preset amount of time. In a preferred embodiment, the systemremains in idle mode for 12 to 72 hours. The use of a rest period is setthrough the programmer at the judgment of the attending healthpractitioner.

However, if no internal healing current is detected or a rest period isnot desired for any other reason, therapy will immediately enter step123 where 50 mV to 1 V is delivered for 4 to 48 hours between an anodeand a cathode. This low voltage field applied at step 123 may attractleukocytes (white blood cells) to the tumor in order to clean updestroyed cells caused by step 119. A voltage of 50 mV is typically highenough to attract leukocytes, but below the electrolysis level. In apreferred embodiment, voltages ranging from 50 mV to 1 V and durationsranging from 4 to 48 hours are useful for attracting leukocytes.

Referring now to FIG. 27 c, another method of the preferred embodimentis shown. The method of FIG. 27 c is useful when using chemotherapy inconjunction with electrical therapy. Beginning at step 124 a remotecathode and/or anode electrode is implanted near the chemotherapyadministration site.

At step 125 a generator is implanted away from the tumor. In a preferredembodiment, the generator is implanted at least 10 cm away. By placingthe generator further away from the tumor than in FIG. 27 a and FIG. 27b, a chemotherapeutic agent may be more effectively directed to a tumorsite. At step 126 the generator is programmed by telemetry. Manyparameters can be programmed such as duration of therapy, duty cycle,pulse width, voltage, current, total coulombs delivered, anode/cathodeswitching, administration regimen of the chemotherapeutic agent, and thelike. The specific parameters described below are only one sequence ofan infinite number of settings, and therefore, should be seen asillustrative only and is in no way limiting.

At step 127 a chemotherapy bolus is administered. Administration of achemotherapeutic agent may be by way of any of a catheter, implanteddrug pump, an injection, an oral dosage, a suppository, a skin patch andany other type of bolus. In a preferred embodiment, a catheter may beimplanted to non-invasively administer drugs to a patient. An implantedcatheter advantageously decreases risk of infection because the skinbarrier is not punctured. Numerous types of catheters may be used inconjunction with the present embodiment and a number of them aredescribed later in the application. Any of the catheters describedtherein may be used with the method of the preferred embodimentdescribed herein. Any drug which enhances amelioration of cancer may beused. In a preferred embodiment bleomycin, mitoxantrone, melphalan,dactinomycin, adriamycin, and/or doxorubicin are used. Selection of thespecific chemotherapeutic agent should be made in conjunction with anelectrical therapy treatment regimen. Alternatively, a drug withspecific properties may be chosen and then an electrical therapy regimencan be adjusted appropriately. For example, designing an electricaltherapy regimen to reduce oxygen, which can be accomplished by makingall of the electrodes slightly or briefly cathodic, will enhance theeffect of doxorubicin.

At step 128 1 to 5 V are delivered between at least one anode and atleast one cathode for 1 to 4 hours. The at least one cathode may be anyof an electrode and a generator housing. The electrical field createdbetween an anode and a remote cathode attracts a (negatively charged)chemotherapeutic agent to the tumor. A chemotherapeutic agent may beattracted to the tumor when the agent is administered in any way. Forexample, the agent may be administered systemically by any means and/ordirectly by any means to the site. By applying the appropriate polarityto a tumor site a charged chemotherapeutic agent is drawn viaiontophoresis to the site, whether systemically or locally administered.In order to effectively attract a charged chemotherapeutic agent to thetumor, the polarity of the tumor should be made opposite of thechemotherapeutic agent's charge. For example, for a negatively chargeddrug, the tumor electrode polarity should be positive and for apositively charged drug (such as, for example, bleomycin andadriamycin), the tumor electrode polarity should be negative. In otherwords, in the case of a negatively charged chemotherapeutic agent,electrical therapy may be applied between an anode electrode implantedin a tumor and a remote cathode. Because the anode electrode drawsnegative charge, the negatively charged chemotherapeutic agent willmigrate towards the anode electrode, thus increasing the concentrationof negatively charged chemotherapeutic agent in the tumor.Alternatively, in the case of a positively charged chemotherapeuticagent, electrical therapy may be applied between a cathode electrodeimplanted in a tumor and a remote anode. Because the cathode electrodedraws positive charge, the positively charged chemotherapeutic agentwill migrate towards the cathode electrode, thus increasing theconcentration of positively charged chemotherapeutic agent in the tumormass.

At step 129 1 to 2 V may be applied in reverse polarity as step 128 for1 to 10 minutes to disperse a chemotherapeutic agent throughout a tumormass. For example, in the case of a negatively charged chemotherapeuticagent, electrical therapy may be advantageously applied between an anodeimplanted into a tumor and a remote cathode as described in step 128.Following concentration of the negatively charged chemotherapeutic agentaround an anode implanted in the tumor as described in step 128,polarity may reverse such that electrical therapy is applied between acathode implanted in the tumor and a remote anode. This step 128advantageously disperses a negatively charged chemotherapeutic agentthroughout the peripheral tumor tissue. In another example, in the caseof a positively charged chemotherapeutic agent, electrical therapy maybe advantageously applied between a cathode implanted into a tumor and aremote anode as described in step 128. Following concentration of thepositively charged chemotherapeutic agent by, for example iontophoresis,around a cathode electrode implanted in the tumor as described in step128, polarity may reverse such that electrical therapy is appliedbetween an anode implanted in the tumor and a remote cathode. This step128 advantageously disperses a positively charged chemotherapeutic agentthroughout the peripheral tumor tissue.

Following steps 128 wherein an ionically charged substance isconcentrated in the tumor area, by for example iontophoresis, and step129, wherein the charged substance is optionally dispersed throughoutthe local tumor area by, for example, reversing polarity, cellularmembranes are rendered permeably via high voltage pulses, such as inelectroporation. In this manner, the ionic substance, such as achemotherapeutic agent is concentrated in a tumor and then the cancerouscells are forced to accept the agent via electroporation.

At step 130 cell membranes are forced open by electroporation with anappropriate electrical therapy regimen. Although there are numerouselectrical ways to force open a cellular membrane, the following is anexample of an appropriate voltage and time duration. At step 130 200 to1300 V for 1 μs to 1 ms may be delivered in repetition 10 to 100 timesbetween at least one anode and one cathode. In one embodiment, the dutycycle may range from 20 percent to 80 percent. Step 130 forces opencancer cell membranes to facilitate entry of drug molecules into cancercells. Electroporation as described in step 130 allows molecularly smalland large chemotherapeutic agents through the cell membrane. However,this step 130 is particularly advantageous for large chemotherapeuticagents because of their size. The device may also be constructed so thatthe device housing can be used as the remote electrode when appropriatewith consideration of patient comfort, safety (e.g. avoiding cardiacfibrillation), and electroporation effectiveness. In another embodiment,electroporation may be achieved via an external power source. Anexternal power source may be coupled to the leads of the implantedelectrical system by a port or any other coupling means for the purposeof supplying appropriate voltages, pulse widths, spacing periods, andrepetitions appropriate for electroporation. This embodiment mayadvantageously reduce the need for high voltage generation circuitry andhigh power supply needed for electroporation.

Referring now to FIG. 27 d, another method of the preferred embodimentis shown. The method of FIG. 27 d is useful when using radiation therapyin conjunction with electrical therapy. Beginning at step 131 one ormore leads containing at least one anode electrode and/or at least onecathode electrode is implanted into, nearby, or adjacent to a tumor. Thelead or leads and electrodes comprised therein may be of anyconfiguration.

At step 132 a generator is implanted away from the tumor. In a preferredembodiment, the generator is implanted several cm at least 5 cm andpreferably 10 cm away while a distance of 3 to 40 cm is workable. Thegenerator should be implanted such that it will not be in the way ofionizing radiation. Alternatively, the generator can be made ofradiation hardened circuitry that can survive the strong radiation. Atstep 133 the generator is programmed by telemetry. Many parameters canbe programmed such as duration of therapy, duty cycle, pulse width,voltage, current, total coulombs delivered, anode/cathode switching, andthe like. The specific parameters described below are only one sequenceof an infinite number of settings, and therefore, should be seen asillustrative only and in no way limiting.

At step 134 5-10 V are delivered between any combination andconfiguration of anode electrode or electrodes and any combination andconfiguration of cathode electrode or electrodes for 0.5 to 2 hours.This step 134 changes pH in the tumor and begins rapid destruction. pHchanges down to about 2 and up to about 13 may be found at the anode andcathode, respectively. A change in the pH of at least 2 may begindestruction. In a preferred embodiment, voltages in the range of 3 to 25V and durations in the range of 10 minutes to 2 hours are useful forchanging the internal tumor pH.

At step 135 polarities of anode or anodes and cathode or cathodes mayoptionally switch as desired during therapy. By switching polaritiesmore consistent tumor destruction may ensue by ensuring that eachelectrode serves as both an anode and as a cathode. Moreover, sometumors shrink more quickly with one polarity versus the other (e.g.anode versus cathode).

At step 136 the generator may optionally begin monitoring voltagebetween the anode and the generator housing. If an internal intrinsichealing current is detected or a rest period is desired for any otherreason, no further therapy is provided until the device is reprogrammed.As a result, the system remains in idle mode at step 137. Alternatively,the device may automatically restart electrical therapy after a presetamount of time. In a preferred embodiment, the system remains in idlemode for 12 to 72 hours as determined by the health practitionerpreference and the patient response.

However, if no internal healing current is detected or a rest period isnot desired for any other reason, therapy will immediately enter step138 where 50 mV to 1 V is delivered for 4 to 48 hours between an anodeand a cathode. This low voltage field applied at step 138 may attractleukocytes (white blood cells) to the tumor in order to clean updestroyed cells caused by step 134. A voltage of 50 mV is typically highenough to attract leukocytes, but below the electrolysis level. In apreferred embodiment, voltages ranging from 50 mV to 1 V and durationsranging from 4 to 48 hours are useful for attracting leukocytes.

At step 139 2 to 10 volts are applied to all electrodes, therebyrendering them anodic for 5 to 30 minutes. (As is readily understood bythose of ordinary skill in the art, the housing or another large remoteelectrode must serve as a current return and hence will be cathodic.)This step 139 increases molecular oxygen concentration. In this case,radiation therapy and/or brachytherapy may be advantageously used inconjunction with increased molecular oxygen to enhance the effects ofboth radiation therapy and/or brachytherapy. Additionally, certainoxygenating substances, such as for example, nitromidazoles andperfluorocarbons, and/or any of the other oxygenating substancesdescribed hereinbelow, may be administered to the tumor site to increaseoxygen concentration.

At step 140 a radioactive material is administered. In a preferredembodiment, the radioactive material may be cobalt-60, iodine-125,iodine-131, iridium-192, strontium-89 (metastron), and samarium-153.

Turning now to FIG. 27 e, another method for use in electrical therapyis described. Beginning at step 1900 an electrical therapy system havingat least one lead and at least one electrode is implanted into and/or inthe periphery of a tumor. At the minimum, the system has a power source,at least one lead, and at least one electrode. However, the system mayalso include any of the numerous types and variations of options suchas, for example, power sources (internal and/or external), electrodes,electrode arrays, leads, fixation means, electrical ports, and druginfusion devices described herein.

At step 1902 the system is programmed. The system may be programmed byany of the means described herein, such as by RF. The system may beprogrammed according to any of the options and parameters describedherein. At step 1904 5 to 100 C per ml tumor tissue is administered. The5 to 100 C may be delivered in any amount of time desired. For example,in DC ablation, the time period may be longer whereas inelectroporation, the time period may be shorter. Following at step 1906,the system may rest for 12-72 hours. Following the rest period, amedical practitioner may review various parameters, such as, forexample, internal pH, oxygen concentration, temperature, and any of theother parameters described herein to determine if additional therapy isrequired. Alternatively, the device, using a closed-loop mechanism, maydetermine if additional therapy is required. The closed-loop parametersmay be any as described herein. If additional therapy is required (ordesired) the system may change polarity at step 1910. Again, a medicalpractitioner may determine if polarity reversal is needed or desired forany reason. Alternatively, the device may determine if polarity reversalis needed or advantageous based on the closed-loop system describedherein. At this point, the anodes may switch to cathodes (and viceversa) dependent on the system and/or medical practitioner's assessment.However, the system and/or medical practitioner may determine thatpolarity reversal in not necessary or desirable. In any case, the systementers step 1904 where 5-100 C per ml tissue is delivered to a tumoragain.

If additional therapy is not needed or desired according to the systemand/or medical practitioner at step 1908 the system enters step 1912. Atstep 1912 the system and/or medical practitioner determines if newlydeveloped tumors are present. The system and/or medical practitioner mayuse imaging, such as described herein, to determine the existence (andlocation if any) of newly generated tumors. If more tumors are detectedthen the system enters step 1914. At step 1914 the system and/or medicalpractitioner determines if the leads should be repositioned. Leads mayneed to be repositioned if additional tumors are located so that thenewly generated tumors may be subjected to electrical therapy. However,if a new tumor is substantially in the same area as an electrode, it maynot be necessary to reposition the lead or leads. In either case, thesystem enters step 1904 where 5-100 C per ml tissue is delivered to atumor again. However, if at step 1912 no new tumors are present, thesystem idles at step 1916 until the system recycles due to closed-loopprogramming, a medical practitioner reprograms the system, or a patientreprograms the system, which may be accomplished by using the patientcontrol mechanisms described herein.

The method of FIG. 27 e may be used in conjunction with chemotherapy andradiation therapy as desired.

Turning now to FIG. 27 f an electrical therapy method using current isdepicted. Beginning at step 1920 an electrical therapy system having atleast one lead and at least one electrode is implanted into and/or inthe periphery of a tumor. At the minimum, the system has a power source,at least one lead, and at least one electrode. However, the system mayalso include any of the numerous types and variations of options such asfor example, power sources (internal and/or external), electrodes,electrode arrays, leads, fixation means, electrical ports, and druginfusion devices described herein.

Following at step 1922 the system is programmed. The system may beprogrammed by any of the means described herein, such as by RF. Thesystem may be programmed according to any of the options and parametersdescribed herein. At step 1924 0.5 to 50 mA are applied to a tumor for1-50 hours. However, step 1924 may be broken up into repeated sequencesof shorter therapies. The period of the shorter therapies may be from 5minutes to an hour and have a duty cycle of 20 to 80 percent. Forexample, 0.5 to 50 mA may be administered using a 20 minute period and a50 percent duty cycle which would result in ten minute increments ofcurrent delivery interspaced with a five minute off period for a totalof 25 hours. This turn off period may allow the healthy peripheraltissue to return to a normal pH, whereas, the cancerous tissue, due toits poor buffering capability, would remain at a high or low pH. Lesscurrent over longer periods of time may be advantageous in certaincircumstances whereas higher current over shorter periods of time may beadvantageous in other circumstances. For example, in DC ablation,current is likely to be lower than in electroporation. Additionally, DCablation is likely to be applied over a longer period of time thanelectroporation.

Following administration of electrical therapy at step 1924, the systemmay rest for 1-72 hours. This rest period may be desirable to allow thetumor to return to a normal pH. This in turn, should allow macrophages,dendritic cells, and other components of the immune system to enter thetumor, ingest dead tumor cells, and possibly present the cancer cellantigens to T cells and other components of the immune system. Followingthe rest period, the device, using a closed-loop mechanism, maydetermine if additional therapy is required. The closed-loop parametersmay be any as described herein. Alternatively, a medical practitionermay review various parameters, such as, for example, internal pH, oxygenconcentration, temperature, and any of the other parameters describedherein to determine if additional therapy is required. If additionaltherapy is required (or desired) the system reenters step 1924 where 0.5to 50 mA are delivered to a tumor for 1 to 50 hours.

However, if additional electrical therapy is not required or desired asdetermined by a closed-loop mechanism or a medical practitioner at step1928, the system enters a rest period for 3 to 10 days at step 1930.Following this second rest period at step 1930 the system againdetermines by way of a closed-loop mechanism or by way of a medicalpractitioner if additional therapy is required or desired for any reasonat step 1932. If additional therapy is required or desired, the systemwill determine, through a closed-loop mechanism or by a medicalpractitioner, if the leads should be repositioned at step 1934. Lead orleads may need to be repositioned if the tumor has changed shape or sizeand/or if new tumors are located. In either case, whether the lead orleads are repositioned or not, the system reenters the electricaltherapy step at 1924 where 0.5 to 50 mA are delivered to a tumor for 1to 50 hours. Importantly, the electrical therapy need not be the sameeach time.

Alternatively, if, at step 1932, no additional electrical therapy isrequired or desired, the system idles at step 1936 until the systemrecycles due to closed-loop programming, a medical practitionerreprograms the system, or a patient reprograms the system, which may beaccomplished by using the patient control mechanisms described herein.

At any time following the rest period and for a period of up to a fewmonths, adjuvants and cytokines may be administered to the patient tosupport the immune system. Examples of agents may includegranulocyte-macrophage colony-stimulating factor (GMCSF),colony-stimulating factors (CSFs), poly-inosinic, cytidylic acid(poly-IC), interleukin-2 (TL-2), and CPG.

The method of FIG. 27 f may be used in conjunction with chemotherapy andradiation therapy as desired.

Electrical therapy can be used separately without the addition ofchemotherapeutic agents, radiation therapy, and brachytherapy. However,electrical therapy in conjunction with chemotherapeutic agents,radiation therapy, and brachytherapy may be advantageous to amelioratecancer more effectively and/or more efficiently than electrical therapyalone. Each of the previously described methods and method stepsillustrated in FIGS. 27 a-27 f may be used in conjunction with eachother for increased effectiveness. For example, chemotherapy andradiation therapy may be used in conjunction with the method forunipolar and/or bipolar treatments.

Importantly, the present embodiment disclosed in each of the preferredmethods is distinct from pacemakers because durations of more than amicrosecond are not attainable by pacemakers. In this case, the presentembodiment requires nearly 1000 times the energy as a typical pacemaker.For example, a 100 mV voltage for one day, with a system impedance of1000 Ohms requires 864 mJ in comparison to a typical pacemaker whichgenerates 1 mJ pulses.

Shown in FIG. 28 a-28 b and FIG. 29 a-29 b are current level profileswhich vary from those described in the preferred embodiments of FIG. 27a-27 d. The abscissa in each of FIG. 28 a-28 b and FIG. 29 a-29 brepresents time, such that a point nearer to the ordinate is less timeand a point further away from the ordinate is more time. The ordinate ineach of FIG. 28 a-28 b and FIG. 29 a-29 b represents current, such thata point nearer to the abscissa is less current and a point further awayfrom the abscissa is more current. Each of FIG. 28 a-28 b and FIG. 29a-29 b start at a baseline 141 which may be described as the normal,unique body current detected in each patient. Dependent on eachpatient's unique baseline current level 141, a therapeutic current level143 of between 50 μA and 25 mA or 50 mV to 25 V will be attained byincreasing the current 142 at a variable rate. Due to the uniquecircumstances of each patient, current may be increased relativelyquickly up to 1 A per second or 1 mA per ms or more gradually at 1 μAper second but more typically around 1 mA per second.

In FIG. 28 a the therapeutic current level 143 is attained by graduallyincreasing the current 142 from the initial baseline 141. Graduallyincreasing current may be advantageous to reduce any potential painexperienced by a patient. In FIG. 28 b therapeutic current 143 isincreased to level 144 between 100 μA and 50 mA in response to an inputfrom a microprocessor and is later restored gradually 145 to itsoriginal value 143. These changes may be in response to a sensor input,to circadian, other body rhythms, and changes in measured heart ratevariability.

FIG. 29 a shows a therapeutic current level 143 and at least oneelectroporation therapy 146 and 147 with an exemplary level of about 2amperes applied at desired times. In a preferred embodiment,electroporation therapies 146 and 147 may be performed in conjunctionwith chemotherapy sessions. Furthermore, electroporation pulses may bebiphasic and may be applied synchronously with a detected heartbeat inorder to reduce the risk of inducing cardiac arrhythmias. Feedback mayalso be used to adjust electroporation parameters. For example, theelectrical consequences of electroporation may be used to adjust thedistribution of the electrical field at the electrodes. FIG. 29 brepresents the use of electrical therapy with a healing signal 149generated within the device. At step 148 the tumor is destroyed. Inresponse, the device applies a healing current 149 to the former tumorsite. The previous examples are only several illustrations of potentialvariations in current level for the present embodiment and are in no waylimiting. Each therapy will vary in terms of current level and/orvoltage level and rate of achieving current level depending on thespecific circumstances, including the patient, therapy regimen, optionsand variations in the device, and other types of therapy usedconcurrently with electrical therapy.

Illustrated in FIG. 30 are examples of therapeutic current paths for atumor located in the upper abdominal region of a human. In this example,the tumor may be located specifically in the liver. Shown are agenerator 1, a tumor 6, a remote cathode 151, an exemplary primarytherapeutic current 152, an exemplary secondary therapeutic current 153,and anode 154, and leads 1800 and 1802. Although the anode 154, theremote cathode 151, and the generator 1 can be placed in variouslocations depending on where the tumor 6 is located, the following areexamples of the preferred placements for the anode 154, the remotecathode 151, and the generator 1 for the tumor 6 located in the upperabdominal cavity of a human as shown in FIG. 30. The primary therapeuticcurrent 152 flows between the anode 154, located inside tumor 6, and thegenerator housing 1, which acts as the primary cathode. The secondarytherapeutic current 153 flows between the anode 154 and the remotecathode 151, which is located in the upper right thoracic region. Morespecifically, the remote cathode 151 may be specifically locateddirectly below the right clavicle. The generator 1 is preferably locatednear the tumor 6 approximately 6-10 cm away and is the cathode for allcurrents except for a current used to direct a chemotherapeutic agent tothe tumor 6. However, if the generator is being used as the remoteelectrode to attract the chemotherapeutic agent to the tumor 6 then itshould be farther away such as 1 to 40 cm away. The generator 1 islocated in the upper left thoracic region, and more specifically may belocated directly below the left clavicle. In this embodiment, it may beadvantageous to locate a remote cathode 151 further away from the tumorthan the generator 1 (cathode) to better direct chemotherapeutic agentsto the anode 154, thereby creating a secondary therapeutic current 153.

5. CHEMOTHERAPY AND RADIATION THERAPY

Although electrical therapy alone is useful in treating cancer, in somecases amelioration of cancer is more effective and/or more efficient inconjunction with chemotherapy and/or radiation therapy. Periodicchemotherapy may be supplied by traditional means independent of anyimplant designed to deliver chemotherapeutic agents. Alternatively, animplant may be designed to supply chemotherapy treatment as well aselectrical stimulation. In one embodiment, a generator contains asubcutaneous port for penetration by a hypodermic needle. A drug can beinfused real time through the port and through a delivery tube into atumor. The delivery tube may be built into a lead or it may be aseparate tube. In another embodiment, a generator contains a reservoirfor storing a drug or drugs. Under control of a timing circuit, thedrug, or drugs, may be released through a tube into a tumor. Thetechnology of implantable drug infusion pumps, ports, and tubes is wellknown to those of ordinary skill in the art. However, the combination ofinfusion pumps, ports, and tubes has not been used in conjunction withelectrical therapy as described herein. A general benefit of combinedelectrical therapy and drug infusion is that, in the practice ofimplantable drug infusion pumps, reservoir and flow limitations dictatethat chemotherapy drugs be highly concentrated. Electrical therapy canadvantageously increase the effectiveness and efficiency of chemotherapydrugs, thus permitting lower concentrations or less frequent reservoirrefilling.

Turning now to FIG. 31-32, a generator/infusion device 155 is depicted.Shown are a tumor 6, the generator/infusion device 155, an infusioncatheter 156, electrodes 157 and 601, a circulatory system 158, acatheter tip 610, and leads 640 and 645. The generator/infusion device155 is coupled to the infusion catheter 156 and leads 640 and 645. Thelead 640 terminates at the end opposite the generator/infusion device155 with electrode 157 and the lead 645 terminates at the end oppositethe generator/infusion device 155 with electrode 601.

The infusion catheter 156 is coupled to an internal reservoir (notshown) of a drug inside the generator/infusion device 155. Thegenerator/infusion device 155 discharges a drug, or drugs, into thecatheter 156. The drug, or drugs, flows through the catheter 156 to thecatheter tip 610 where the drug, or drugs, is delivered to the tumor 6or the circulatory system 158.

The electrodes 157 and 601 are electrically connected to thegenerator/infusion device 155 via leads 640 and 645 such that theelectrodes 157 and 601 may be of either polarity, i.e. anode or cathode.Additionally, electrodes 157 and 601 may switch polarities as previouslydescribed hereinabove. In one embodiment, the generator/infusion device155 may switch the polarities of electrodes 157 and 601 via internalcircuitry such as described in FIG. 2 e-2 f hereinabove. Moreover, thegenerator/infusion device 155 may additionally serve as the anode orcathode, in place of, or in addition to electrodes 157 and 601. Theelectrodes 157 and 601 are located inside or peripheral to tumor 6. Inthe present embodiment, the electrode 157 is located at the tumor 6periphery and the electrode 601 is located inside of tumor 6. However,electrodes 157 and 601 may be placed in any location relative to thetumor 6 useful for the treatment of cancer via electrical therapy.Furthermore, any combination of unipolar, multipolar, electrode arrays,and/or any other variation and configuration available for use withelectrical therapy is contemplated by the inventors for use with thegenerator/infusion device 155 of the present embodiment.

The infusion catheter 156 can be inserted directly into the tumor 6, asshown in FIG. 31. Alternatively, as shown in FIG. 32, the infusioncatheter 156 can be positioned to infuse drugs to remote locations, suchas into a vein or artery of the circulatory system 158. In anotherembodiment, hepatic artery infusion can be used for liver malignancies,whereas venous infusion is preferred for many other cancers.

To ameliorate pain associated with cancer, morphine may be administeredintrathecally with the device of the present embodiment. Moreover,subdural and intra-peritoneal infusion may also be used.

In another embodiment, more than one drug reservoir can be utilized toadminister several drugs or to store increased amounts of the same drug.More than one drug reservoir may be inserted into a singlegenerator/infusion device by separating the drug reservoir compartments,whereas a separate infusion device may also be used in conjunction witha generator/infusion device containing a single drug. In the case ofadministering more than one drug, the drugs can be infused on separateschedules and the patient may be given control over one drug but not theother. For example, the patient may have control over administration ofa pain killer, such as morphine. However, the patient may not havecontrol over the chemotherapeutic agent. Alternatively, several drugreservoirs may be used to increase the amount of chemotherapeutic agenton reserve, which leads to less frequent reservoir refilling.

Depicted in FIG. 33 is a drug infusion device 161 that is physicallyseparated from a generator 1. Shown are the generator 1, a tumor 6,electrodes 159 and 615, a control/communication path 160, an infusiondevice 161, a target site 162, a catheter 163, a catheter tip 607, andleads 650 and 655.

The generator 1 is coupled to leads 650 and 655. The lead 650 terminatesat the end opposite the generator 1 with electrode 159 and the lead 655terminates at the end opposite the generator 1 with electrode 615. Theelectrodes 159 and 615 are electrically connected to the generator 1such that the electrodes 159 and 615 may be of either polarity, i.e.anode or cathode. Additionally, electrodes 159 and 615 may switchpolarities as previously described hereinabove. In one embodiment, thegenerator 1 may switch the polarities of electrodes 159 and 615 viainternal circuitry such as described in FIG. 2 e-2 f hereinabove.Moreover, the generator 1 may additionally serve as the anode orcathode, in place of, or in addition to electrodes 159 and 615. Theelectrodes 159 and 615 are located inside or peripheral to the tumor 6.In the present embodiment, the electrode 159 is located at the tumor 6periphery and the electrode 615 is located inside of tumor 6. However,electrodes 159 and 615 may be placed in any location relative to thetumor 6 useful for the treatment of cancer via electrical therapy.Moreover, any combination of unipolar, multipolar, electrode arrays,and/or any other variation and configuration available for use withelectrical therapy is contemplated by the inventors for use with thepresent embodiment.

The catheter 163 is coupled to an infusion device 161. The infusiondevice 161 contains a drug reservoir (not shown), or reservoirs—for theadministration of one or more drugs as described hereinabove). Theinfusion device 161 discharges a drug, or drugs, into the catheter 163.The drug, or drugs, flows through the catheter 163 to the catheter tip607 where the drug, or drugs, is delivered to the target site 162. Thetarget site 162 can be any of a vein, artery, hepatic artery, the tumor6, and the tumor 6 periphery.

The generator 1 can control the infusion device 161 via thecontrol/communication path 160 or vice versa. For example, the generator1 may communicate a start or stop function to the infusion device 161via control/communication path 160 in order to synchronize chemotherapywith electrical therapy. In one embodiment, synchronization can beprogrammed into each of the generator 1 and the infusion device 161whereby each performs a function at a given time. The generator 1 cansense the infusion device 161 activity by monitoring various types ofsensors. For example, in the case that the infusion device 161 cathetertip 607 is at the tumor 6 (not shown), a fluid sensor in the lead tipnear the electrode 615 can sense the amount of chemotherapeutic agentinfused. Alternatively, a pH sensor can be used to detect the amount ofchemotherapeutic agent administered. Or, in another embodiment, as pH issensed, certain chemotherapeutic agents may be advantageouslyadministered. For example, the chemotherapeutic agent mitoxantrone iseffective at basic pH values. Therefore, a pH sensor of the presentembodiment may detect a basic or acidic pH value and appropriately senda signal to the infusion device 161 to automatically administermitoxantrone when pH values are basic and stop administration ofmitoxantrone when pH values are acidic. Alternatively, a pH sensor ofthe present embodiment may advantageously signal an operator when a highenough pH has been reached to manually administer mitoxantrone. Becausemany chemotherapeutic agents are charged, either positively ornegatively, the sensed charge is proportional to the amount of drugeffectively reaching the tumor. This type of detection can be used inclosed-loop control. In another embodiment, the sound of a pump, such asperistaltic rollers and solenoid action, associated with infusion device161 can be detected by a sound sensor. In yet another embodiment, thephysiological effects of the chemotherapeutic agent are detected.Conversely, the infusion device 161 may be designed to sense thegenerator 1. Or, both the infusion device 161 and the generator 1 cansimultaneously sense each other. Communication between the devices isachieved with a program code which is sent from one device to the othervia the control/communication path 160. Alternatively, a hardwiredelectrical connection is made at tumor site 6.

Although synchronizing a generator and an infusion device duringelectrical therapy may be advantageous, other types of synchronizationare also envisioned for use in another preferred embodiment. Forexample, numerous closed-loop approaches are available for use inelectrical therapy, such as controlling therapy based on sensedparameters including oxygen levels, impedance across or within a tumor,pH levels, and internal voltages measured in electrodes employed inelectrical therapy.

With regard to sensed oxygen levels, therapy may be modified based onthe concentration of oxygen in and around a tumor. Oxygen may bemonitored and measured with any of the devices and methods describedabove, such as by using optical fibers; however, any other device andmethod useful to quantify oxygen concentration may be used. For example,another method includes tracking DC voltage and/or current between thesystem electrodes (which may be made of various types of precious metalsuch as gold and platinum) and an implanted device housing (which may bemade of a partial carbon surface, partial platinum surface, and/or apartial titanium surface) that serves as a reference point. In practice,DC voltage and/or current may be tracked in and around a tumor between agold electrode (inserted in or around the tumor) and a device housingpartially surfaced with carbon.

In the case of sensed impedance, electrical therapy may be modifiedbased on the impedance measured across or within the tumor as a functionof frequency. Impedance may be sensed by having a driver, such as theones depicted in FIG. 22 and FIG. 23, emit a small AC current for themeasurement of impedance (when electrical therapy is in DC current).Alternatively, AC current may be used to measure impedance whenelectrical therapy is briefly turned off. In one example, atomic oxygenin the gaseous form can be measured by impedance spectrum due to thediffering frequency dependent impedances generated by various gases andfluids. Therefore, by examining impedance as a function of frequency,oxygen level may be determined. If in the case that a high level of“free” or gaseous oxygen is measured, the system may be programmed todecrease the amount of current applied. This is largely because excessgas can cause pain and/or bloating in a patient. Alternatively, inanother circumstance, increased oxygen may be indicative of growingtumors as they tend to have a large oxygen supply. Sensing oxygen forthis purpose will allow electrical therapy to be adjusted accordingly.

Electrical therapy may also be modified or adjusted in relation to asensed pH. pH may be sensed with any of the devices and methodsdescribed herein above, as well as any other devices and methods usefulfor sensing pH. In practice, sensors may measure pH during applicationsof persistent, high current electrical therapy, such as, for example,during application of 5-10 V for 0.5 to 2.0 hours as described in FIGS.27 a, 27 b, and 27 d. The system may increase current slowly andsteadily over a period of time while simultaneously measuring pH. At thepoint when the sensed pH is equal to a predetermined level (e.g. 2.0)the system may modify current such that the sensed pH stays at exactly2.0 by increasing or decreasing current or, alternatively, may modifycurrent such that the sensed pH is increased or decreased below 2.0 byincreasing or decreasing current. In another embodiment, when the sensordetects a pH of 2.0, electrical therapy may quickly start applyingpersistent, low current electrical therapy, such as, for example,applications of 50 mV to 1 V for 4-48 hours as described in FIGS. 27 a,27 b, and 27 d. Current regulation may require careful PID (position,integral, derivative) controls due to time dependence of the pH on thecurrent application history.

In another embodiment, electrical therapy may be adjusted based oninternal voltages detected inside a tumor. A tumor is generallyelectronegative in comparison to healthy tissue. For example, tumortissue has been described as being approximately 5 to 8 mV moreelectronegative than normal or healthy tissue. Therefore, implantedelectrodes may sense the internal tumor voltage and adjust electricaltherapy accordingly. For example, if tumor voltage is moreelectronegative than the surrounding healthy tissue, electrical therapymay be increased (e.g. increase total coulombs delivered, current,and/or voltage). However, if tumor voltage is neutral or positive incomparison to healthy tissue, then electrical therapy may be reduced orhalted locally or globally (e.g. decreased total coulombs delivered,current, and/or voltage).

A method of passive synchronization is depicted in FIG. 34. Passivesynchronization can be achieved by cycling the infusion device 164 atregular intervals so that the implanted generator 166 can measure thefirst interval and then start its output prior to the start of the nextinterval. The passive synchronization model described in FIG. 34 isdesigned with external patient controllers 168 and 170, so that theinfusion device 164 and implanted generator 166 can be adjustednon-invasively through the skin 172. In another embodiment, the externalpatient controllers 168 and 170 can be designed to communicate with oneanother and thus control synchronization of the infusion device 164 andimplanted generator 166. In yet another embodiment, the controllers 168and 170 can be combined into one unit. In another embodimentsynchronization can also be applied in continuous or bolus mode.

Chemotherapeutic agents and other pharmaceuticals to be used inconjunction with the present embodiment can be administered variablyaccording to circadian rhythms. As is known to those of ordinary skillin the art, efficacy and toxicity of commonly used chemotherapeuticagents correspond to the time of administration. For example, dosagescapable of killing tumor cells may also kill or severely injure normaltissues. However, the susceptibility of normal tissues to powerfulchemotherapeutic agents varies rhythmically depending on the circadiancycle, while tumor cells display a different time-related response.Thus, the timing of drug delivery is important for achieving therapeuticspecificity. Therefore, administering chemotherapeutic agents and/orother pharmaceuticals may be advantageous because this practicemaximizes dosage with minimal toxicity. Electrical therapy can also beadjusted according to the same circadian rhythm for maximumeffectiveness. In a preferred embodiment, patients are treated with aconsistent dosage of chemotherapeutic agent and electrical therapy on aregular schedule. As is known by those of ordinary skill in the art,these factors, consistent dosage and regular schedule, are important tothe ultimate success of chemotherapy.

Turning now to FIG. 35 a-35 f, several catheter designs used to deliverdrugs at a target site are illustrated. Shown are a fixation means 171,a catheter 172, a catheter tip 173, an electrode 174, an internal lead175, an external lead 176, an electrode array 177, and apertures 178.Each of the catheters depicted in FIG. 35 a-35 f are coupled to aninfusion device (not shown). The infusion device may be implanted into apatient or located externally to the patient. Additionally, the infusiondevice may have a single drug reservoir or multiple reservoirs for theadministration of various pharmaceuticals. The infusion device (notshown) discharges a drug, or drugs, into the catheter 172. The drug, ordrugs, flows through the catheter 172 to the catheter tip 173 where thedrug, or drugs, is delivered to the target site. The target site may beany of a tumor, tumor periphery, a vein, an artery, a hepatic artery,and the like.

The catheter of FIG. 35 a has a fixation means 171 coupled to thecatheter tip 173 end. The fixation means 171 may be any means sufficientto directly or indirectly anchor a catheter to tissue, such as a hook,needle, suture, clamp, screw, prong, telescoping regions, and the like.

The catheter of FIG. 35 b combines the electrode 174 with the catheter172. The catheter 172 of FIG. 35 b is capable of concomitantlydelivering chemotherapy and electrical therapy. The electrode 174 iselectrically coupled to an internal and/or external power source (notshown) via the internal lead 175; the lead 175 runs internally throughthe catheter 172.

Alternatively, the electrode 174 may be electrically coupled to a powersource via an external lead 176 as shown in FIG. 35 c. The external lead176 may be wrapped around the catheter 172, as shown. In anotherembodiment, the external lead 176 may run parallel to the catheter 172.An external lead 176 may be sufficient in cases where little mechanicalstress is expected on the catheter 172 and/or lead 176 post-implant. Thecatheter 172 of FIG. 35 c is capable of concomitantly deliveringchemotherapy and electrical therapy. The electrode 174 is electricallycoupled to an internal and/or external power source (not shown) via theexternal lead 176.

An electrode array 177 may be used in combination with a catheter 172,as shown in FIG. 35 d. The electrode array 177 is electrically coupledto an internal and/or external power source (not shown) via an internallead 175. However, an external lead 176, as shown in FIG. 35 c, may alsobe used to couple the electrode array 177 to a power source (not shown).Although two electrodes 174 are shown in the electrode array 177 of FIG.35 d, any number and configuration of electrodes may be used.

The catheter 172 of FIG. 35 e is designed with multiple apertures 178for access to different parts of a target site. In a preferredembodiment, the target site of FIG. 35 e is a tumor or tumor periphery.In one embodiment, the catheter of FIG. 35 e may be advantageously usedin tumor area to deliver varying amounts of a drug to different sites inand around the same tumor according to the size, shape, and othercharacteristics of the tumor. However, the branches and/or apertures 178may be designed to provide the same, or different, amounts of drug ateach site. Any number of apertures 178 and/or branches can be used.Additionally, any number of apertures 178 may be used on various shapedcatheter tips 173 to deliver a drug, or drugs, such as the partial ringstructure catheter tip 173 with four apertures 178 shown in FIG. 35 f.

Any combination of the previously described variations and features maybe used in combination with electrical therapy. The above should beviewed as examples of the numerous variations available and in no waylimiting. The catheter of the present embodiment may be used incombination with electrodes or separate from electrodes and any numberand configuration of electrodes may be used. Leads may be internal orexternal to the catheter. Multiple apertures and fixation means may beused interchangeably between various types of catheters.

The catheter designs illustrated in FIG. 36 a-36 c include porousdrug-absorbing material, which can be laid out over a tumor. Shown are atumor 6, a catheter 172, porous material 179, electrodes 180, andcatheter tip 620. The catheters of FIG. 36 a-36 c are coupled to aninfusion device (not shown). The infusion device (not shown) may beimplanted into a patient or located externally to the patient.Additionally, the infusion device (not shown) may have a single drugreservoir or multiple reservoirs for the administration of variouspharmaceuticals. The infusion device (not shown) discharges a drug, ordrugs, into the catheter 172. The drug, or drugs, flows through thecatheter 172 to the catheter tip 620 where the drug, or drugs, isdelivered to the porous material 179. The electrodes 180 of FIG. 36 b-36c are electrically coupled to an internal and/or external power source(not shown) via a lead or leads (not shown). The lead, or leads, may beelectrically coupled with any number and configuration of electrodes180. The lead, or leads, (not shown) may be internal and/or external tothe catheter.

To aid in dispersing a drug, or drugs, from the catheter 172, porousmaterial 179 is laid over the tumor 6, as shown in FIG. 36 a. The drug,or drugs, dispersed by the catheter 172 is partially absorbed by theporous material 179. In this manner, the tumor 6 remains in contact withthe drug, or drugs, for a longer period of time. In FIG. 36 b the porousmaterial 179 is used in combination with electrodes 180. The electrodes180 may be organized into concentric rings for electrical treatment,such as illustrated in FIG. 36 b. In another embodiment, multiple pointelectrodes 180 may be spread on porous material 179, as shown in FIG. 36c.

The porous material 179 of the present embodiment may comprise any shapeand size appropriate for each circumstance dependent on factors such as,but not limited to, location and size of tumor. Additionally, the porousmaterial 179 may or may not be used in combination with electrodes 180.Electrodes 180 used in combination with the porous material 179 maycomprise any number and configuration of electrodes.

As illustrated in FIG. 37 a-37 c, an electrode array 182 can be used tosteer or spread charged drugs, which are provided by a catheter 172.Shown are the catheter 172; a negatively charged drug 181; the electrodearray 182; individual electrodes 183, 184, and 185; and a catheter tip620. In each of FIG. 37 a-37 c the catheters 172 are coupled to aninfusion device (not shown). The infusion device (not shown) may have asingle drug reservoir or multiple reservoirs for the administration ofvarious pharmaceuticals and/or other solutions. The infusion device (notshown) may be implanted into a patient or located externally to thepatient. The infusion device (not shown) discharges a drug, or drugs,into the catheter 172. The drug, or drugs, flows through the catheter172 to the catheter tip 620 where the drug, or drugs, is delivered to atarget site. In one embodiment, the pharmaceutical is a negativelycharged drug 181 or a positively charged drug (not shown).

The electrodes 183, 184, and 185 of FIG. 37 a-37 b are electricallycoupled to an internal and/or external power source (not shown) via alead or leads (not shown). The lead, or leads (not shown), may beelectrically coupled with any number and configuration of electrodes.The lead, or leads, (not shown) may be internal and/or external to thecatheter. The electrodes 182, 183, and 184 may be of either polarity,i.e. anode or cathode. Additionally, electrodes 182, 183, and 184 mayswitch polarities as previously described hereinabove. In oneembodiment, the generator 1 may switch the polarities of electrodes 182,183, and 184 via internal circuitry such as described in FIG. 2 e-2 fhereinabove. Moreover, the generator 1 may additionally serve as theanode or cathode, in place of, or in addition to electrodes 182, 183,and 184. The electrodes 182, 183, and 184 may be located inside orperipheral to the tumor 6. Furthermore, any combination of unipolar,multipolar, electrode arrays, and/or any other variation andconfiguration available for use with electrical therapy is contemplatedby the inventors for use with the present embodiment.

In FIG. 37 a a negatively charged drug 181 flows from catheter 172towards the center of electrode array 182, in the direction ofpositively charged electrode (anode) 184. However, by alteringelectrical output to various electrodes 183, 184, and 185 in theelectrode array 182, charged drugs can be steered to a desired location.For example, in FIG. 37 b, positively charged electrode 183 is turnedon, while electrodes 184 and 185 are turned off or are turned on ascathodes. Thus, the negatively charged drug 181 is attracted to theelectrode 183. Alternatively, to direct the negatively charged drug 181in the opposite direction, positively charged electrode 185 is turnedon, while electrodes 183 and 184 are turned off (or are turned on ascathodes). Thus, the negatively charged drug 181 is redirected toelectrode 185, as shown in FIG. 37 c. Although the previous exampleswere explained in context of a negatively charged drug, it should beunderstood that a positively charged drug can also be directed accordingto altering charges in an electrode array. While the negatively chargeddrug will be attracted to a positively charged electrode (anode) andrepelled by a negatively charged electrode (cathode), a positivelycharged drug will behave in the opposite fashion. That is, a positivelycharged drug will be attracted to a negatively charged electrode(cathode) and will be repelled by a positively charged electrode(anode). Additionally, any number, arrangement, and configuration ofelectrodes can be used to direct charged chemotherapeutic agents and/orother charged pharmaceuticals.

An application of the electrode array/catheter design of FIG. 37 a-37 cis illustrated in FIG. 38 a-38 b. Shown are a tumor 6; a catheter 172; apositively charged drug 186; individual electrodes 187, 188, and 189; anelectrode array 190; and a catheter tip 620.

The catheter 172 is coupled to an infusion device (not shown). Theinfusion device (not shown) may have a single drug reservoir or multiplereservoirs for the administration of various pharmaceuticals. Theinfusion device (not shown) may be implanted into a patient or locatedexternally to the patient. The infusion device 30, (not shown)discharges a drug, or drugs, into the catheter 172. The drug, or drugs,flows through the catheter 172 to the catheter tip 620 where the drug,or drugs, is delivered to a target site. In one embodiment, thepharmaceuticals are a positively charged drug 186 or a negativelycharged drug; shown in this example is a positively charged drug 186.The electrode array 190 of FIG. 38 a-38 b is electrically coupled to aninternal and/or external power source (not shown) via a lead or leads(not shown). The lead, or leads, may be electrically coupled with anynumber and configuration of electrodes, although in the presentembodiment the electrode array 190 is comprised of three individualelectrodes 187, 188, and 189. The lead, or leads, (not shown) may beinternal and/or external to the catheter.

In FIG. 38 a the positively charged drug 186 initially flows from thecatheter 172 to the center of the electrode array 190 where the tumor 6is located. As therapy continues, the tumor 6 shrinks and its mass is nolonger located at the center of the electrode array 190. Therefore, thenegatively charged electrode (cathode) 189 is turned on and electrodes187 and 188 are either turned off (or are turned on as anodes). Thus,the positively charged drug 186 is directed to tumor 6, which is locatednear electrode 189.

Detection of tumor shrinkage may be detected by sensors contemplatedhereinabove. Also, the presence of the drug changes may alter tumorimpedance and, therefore, electrical load on the generator. These sensedparameters can be used in locating optimum locations for drug steering.The embodiment of electrode drug steering can also be applied to druginfusion for non-cancer applications.

Depicted in FIG. 39 is an electrophoretic drug pump 700, which isfurther explained in U.S. Pat. No. 4,639,244 granted to Rizk in 1987entitled, Implantable electrophoretic pump for ionic drugs andassociated methods, incorporated herein by reference. Shown are areservoir 702, a membrane 708, electrodes 710 and 712, a power source714, an anode lead 716, a cathode lead 718, and drug flow 720.

The reservoir 702 is sealed and contains a drug or drugs to bedispensed. In a preferred embodiment, the drug, or drugs, is ionic (i.e.a drug with an overall positive or negative charge). The drugs mayconventionally be in the form of a suspension. The membrane 708 willpermit ions to pass therethrough. However, the membrane 708 preferablyresists the passage of bacteria therethrough. The membrane 708 may be acellulose membrane. Among the preferred materials that are suitable foruse as the membrane 708 are those made from cellulose esters, nylonpolyvinylidene fluoride, polytetrafluoroethylene, cellulose nitrate andacetate and mixtures thereof. The membrane 708 of the preferredembodiment may have pore sizes from about 0.025 to 8 microns and arefrom about 100 to 200 microns thick. The diameter of the membrane 708 ispreferably between about 13 and 293 millimeters. In general, many typesof microfiltration membranes may be employed. Among the preferredmaterials are those sold under the trade designations “MF” (Millipore);“Celotate” (Millipore); “Durapore” (Millipore); “Diaflow” (Amicon);“Mitex” (Millipore); and “Fluoropore” (Millipore).

The electrodes 710 and 712 may be composed of any of the materialsdescribed hereinabove and/or selected from any of the group consistingof silver/silver chloride, carbon, carbon mesh, and platinum.

Disposed on opposite sides of the membrane 708 and operativelyassociated therewith is a pair of porous electrodes 710 and 712. A powersource 714 is coupled to the anode lead 716 and the cathode lead 718,which thereby energizes the respective electrodes 710 and 712. In thisarrangement, if a negatively charged drug is contained within thereservoir 702 the membrane 708 will permit passage of the negativelycharged drug through the membrane 708. The direction of drug flow 720caused by electrophoresis with the electrodes energized as shown isindicated by the drug flow 720 arrow.

Under normal circumstances, the buildup of a concentration of ions inthe reservoir 702 will result in passage of the material through themembrane 708 in the direction indicated by the arrow representing drugflow 720 even when the electrodes are not energized. This diffusion flowmay be relied upon, in some instances, as establishing a basic rate forongoing delivery of the ionic drugs. In some cases it may be desirableto provide a greater flow than would occur through diffusion in whichcase energizing the electrodes 710 and 712 serves to increase the rateof delivery of the material. If desired, for certain materials, meansmay be provided for reversing the polarity of electrodes 710 and 712 (asdescribed hereinabove) thereby causing the electrophoresis to retard theamount of ionic flow effected through diffusion. Also contemplated isreversing the polarities of the electrodes 710 and 712 to permitdiffusion of a positively charged drug. As will be appreciated by thoseof ordinary skill in the art, the polarities of the electrodes 710 and712 may be either anodic or cathodic in order to allow drug flow 720 ofa negatively or positively charged drug.

The electrophoretic pump of FIG. 39 is contemplated by the inventors foruse with several embodiments described herein.

Represented in FIG. 40 is an example of an incorporation of theelectrophoretic drug pump 700 of FIG. 39 into an electrical therapy andelectrochemotherapy device. Shown are a reservoir 195, leads 196 and796, electrodes 197 and 797, porous extensions 198 and 798, a membrane193, and drug flow 194.

FIG. 40 illustrates an example of an implantable drug pump for use withelectrical therapy. The electrodes 197 and 797 are electrically coupledto a power source (not shown) via leads 196 and 796. The power source(not shown) may be located internally and/or externally to a patient.The electrodes 197 and 797 may be of either polarity, i.e. anode orcathode. Additionally, electrodes 197 and 797 may switch polarities aspreviously described hereinabove. In one embodiment, the power source(not shown) may switch the polarities of electrodes 197 and 797 viainternal circuitry such as described in FIG. 2 e-2 f hereinabove.

The reservoir 195 is sealed and contains a positively or negativelycharged drug. The membrane may be of any of the specifications describedhereinabove as well as any other useful variation.

The porous extensions 198 and 798 of electrodes 197 and 797 frame themembrane 193 periphery on opposite sides thereby permitting or retardingdrug flow 194. The electrodes may be of any of the specificationsdescribed hereinabove as well as any other useful variation.

The ionic drug (that is either positively or negatively charged) willflow through the membrane 193 in the direction of the drug flow 194arrow according to the amount of current supplied, the polarities ofelectrodes 197 and 797, and the charge density of the drug to bedispersed, and type of charge of the drug to be dispersed (i.e.positive, negative, or neutral).

The inventors contemplate using the same principles described herein toany other electrode configuration including the numerous configurationsdescribed hereinabove.

Turning now to FIG. 41 a-41 b, an example of a catheter 850 with anelectrophoretic drug pump is described. FIG. 41 a is in side view andFIG. 41 b is in cross-sectional side view. Shown are a membrane 193,drug flow 194, a reservoir 195, electrodes 199 and 799, leads 196 and396, electrode-lead contact 201 and 801, the catheter 850, polymercoated sections 815, and porous extensions 200.

Shown in FIG. 41 a electrodes 199 and 799 are bands encircling thecircumference of the catheter 850. Interposed between electrodes 199 and799 are polymer coated sections 815. Both electrodes 199 and 799 may beinserted into tissue or, alternatively, only electrode 199 may beinserted into tissue. In a preferred embodiment the tissue is a tumor.Covering the end of the catheter 850 is the porous extension 200 ofelectrode 199 that regulates the rate of drug flow 194.

Shown in FIG. 41 b the electrodes 199 and 799 are coupled to leads 196and 396 at the electrode-lead contact 201 and 801, respectively. Theelectrode-lead contact 201 and 801 may be a weld or any other meanssufficient to couple the electrodes 199 and 799 to the leads. The end ofleads 196 and 396, opposite the electrodes 199 and 799, is coupled to apower source (not shown). The power source (not shown) may be locatedinternally and/or externally to a patient. The electrodes 199 and 799may be of either polarity, i.e. anode or cathode. Additionally,electrodes 199 and 799 may switch polarities as previously describedhereinabove. In one embodiment, the power source (not shown) may switchthe polarities of electrodes 199 and 799 via internal circuitry such asdescribed in FIG. 2 e-2 f hereinabove.

The catheter contains a reservoir 195 of a drug. The reservoir 195 issealed and contains a positively charged drug, a negatively chargeddrug, or a neutral drug. The membrane 193 is located behind the porousextension 200 of electrode 199. The membrane 193 may be of any of thespecifications described hereinabove as well as any other usefulvariation. The porous extension 200 of electrode 199 regulates the rateof drug flow 194.

The liquid emitted by the infusion pumps need not necessarily be a drug.For example, an ionized solution, such as saline solution, can beintroduced into a tumor via the infusion pumps as described hereinabovein order to lower the electrical impedance between electrodes and thusincrease the current flow for a given applied voltage.

In the case of the present invention, electrochemical therapy may beapplied using lower levels of electrical energy if an ionized solution,such as for example, a saline solution, is maintained at the tumor forthe duration of the therapy, which may be months. Electrical therapy,applied briefly at wide intervals, may benefit from the increasedconductivity at the time of application of the pulses via the use ofless electrical energy and possibly less patient discomfort, if there isany. The ionized solution may be stored in liquid form in an implantedpump, such as described hereinabove, and delivered via catheters orneedle electrodes in the manner described hereinabove for drugs, eithercontinuously or intermittently depending upon the desired therapy.Alternatively, a solid ionized substance, such as for example, sodiumchloride, may be introduced into the tumor environment and dissolved inthe water and other fluids present in the tumor prior to and during thetherapy.

Shown in FIG. 42 a-42 b is a device for infusing a solid ionizedsubstance, such as sodium chloride (NaCl) for increased conductivity andreduced impedance in a tumor. Shown are a tumor 504, a lead and/orelectrode 800, a tip 801, solid ionized substance 802, lead and/orcatheter outlets 903 and 904. Turning to FIG. 42 a, the tip 801 of alead or electrode 800 is coated with solid ionized substance 802. Whenthe tip 801 is placed in an aqueous tumor environment, the solid ionizedsubstance 802 slowly dissolves to maintain a higher electricalconductivity in the area. The tip 801 may be designed to assure that allof the solid ionized substance 802 will not be dissolved for months.This may be accomplished by mixing in or coating the solid ionizedsubstance 802 with an agent that inhibits dissolving. In anotherembodiment, the density of the solid ionized substance 802 may beincreased to retard dissolving.

Turning now to FIG. 42 b a device and method useful to direct theionized substance 802 to the center of the tumor 504 is depicted. Thetip 801 is extended beyond electrode and/or drug infusion outlets 903and 904 which are placed in the tumor 504 periphery. Therefore, thesolid ionized substance 802, separated electrically from the electrodeand/or drug infusion outlets 903 and 904 will dissolve in the center ofthe tumor 504 between the electrode and/or drug infusion outlets 903 and904. This will effectively increase the conductivity along the currentpath through the tumor 504. Alternatively, tip 801 may be supplied withorifices for infusing ionized substance through a catheter.

Shown in FIG. 43 is a device for using electrical therapy on tumors withan optical fiber. Shown are a generator 1, a tumor 6, a light source202, and an optical fiber 203. The light source 202 is housed in thegenerator 1. The light source 202 is coupled to the optical fiber 203.The generator 1 powers the light source 202, such that light istransmitted to the tumor 6 by way of the optical fiber 203.

The light transmitted to the tumor 6 from light source 202 may activatea photosensitive drug. For example, a photosensitive cytotoxic drug canbe administered to the tumor 6 by any means, including, but not limitedto, an injection and any of the catheters described herein. Then, at thetumor 6, where light is provided by the light source 202 via the opticalfiber 203, the photosensitive cytotoxic drug is activated; thereby,destroying cancerous cells while preserving healthy cells.

Importantly, it is not necessary for the light source 202 to be housedinside generator 1. That is, the light source 202 may be locatedexternally to the generator 1.

An apparatus and method for treating a neoplasm with an optical fiberpipe is described in U.S. Pat. No. 6,021,347 entitled, Electrochemicaltreatment of malignant tumors, granted to E. Herbst et al, on Feb. 1,2000, which is incorporated herein by reference. However, Herbst doesnot describe using an optic fiber in conjunction with an implantabledevice or electrical therapy as is described herein.

The device of FIG. 44 represents a cross-sectional side view of aconnection means useful for providing power to a light source, which mayactivate photosensitive drugs. Shown are a port 204, skin 205, aconducting needle 206, a needle contact 207, a light source 208, and aconnection to a power supply 209.

The connection to a power supply 209 is coupled to a power source (notshown). In a preferred embodiment, the power source (not shown) is anexternal generator. The port 204 is implanted subcutaneously, below theskin 205 layer. The port 204 is electrically coupled to the light source208. When a conducting needle 206 is inserted into the port 204 andcontacts the needle contact 207 an electrical connection is made betweenpower supply connection 209 and the light source 208, thereby poweringlight source 208. The powered light source 208 is then capable ofdelivering light to a tumor. Light may be delivered to a tumor by way ofan optical fiber, or any other means useful for transmitting light.

This system of powering a light source through an external source may beadvantageous in certain circumstances because light requires a lot ofenergy. This device may conserve internal power supply. Additionally, ifphotosensitive drugs are cytotoxic to all cells, including healthy cellsclose control should be maintained over the light source which may beaccomplished via an external power supply.

The implantable device may be used in conjunction with radiation andchemotherapy. By employing electrical therapy over a long period of timeit helps kill some malignant cells that have developed resistance toradiation and/or to anticancer drugs. The implant can be used to aid ingene transfer therapy and electroimmunotherapy as well as in conjunctionwith vasoconstriction drugs. The implantable device can be used withhyperthermia therapy, ultrasonics, and magnetotherapy as well.

In the case of radiation therapy and/or brachytherapy, the electrodes ofthe present embodiment can be adjusted to enhance the effects ofradiation therapy and/or brachytherapy. At certain points in electricaltherapy, especially in those cases involved with conjunctive radiationtherapy and/or brachytherapy, all electrodes may be forced anodal,thereby generating molecular oxygen. By increasing the concentration ofmolecular oxygen, tissue will be more sensitive to radiation therapyand/or brachytherapy. Additionally, electrical therapy may beadministered until an appropriate oxygen level to enhance radiationtherapy is achieved. The system may detect oxygen level via variousmethods and sensors described herein. Once the appropriate oxygen levelis reached, the system may notify a medical practitioner through atelemetry link to begin radiation therapy.

In another embodiment, tumor cells may be oxygenated with certainoxygenating products such as nitromidazoles (e.g. nimorazole),perfluorocarbons (PFC's) (e.g. Oxyfluor, Oxygent), hypoxic cytotoxins(e.g. tirapazamine, porfiromycin), and RSR13, which is an allostericinhibitor of hemoglobin. These, or other radiosensitizing/tissueoxygenating substances may be infused via a drug pump such as any of thedevices described hereinabove, and/or any other useful device fordelivering a radiosensitive/tissue oxygenating substance to a tumorsite.

Because the electrodes may be placed entirely in a tumor, as previouslydescribed, the cancerous tissue, as opposed to healthy tissue, will besubjected to increased sensitivity to radiation therapy and/orbrachytherapy by any of the methods described hereinabove.

As is known in the art, brachytherapy is a type of radiation therapythat involves the placement of radioactive sources either in tumors ornear tumors. In this treatment approach, radiation from the radioactivesources is emitted outward and is limited to short distances. Thus,unlike external beam radiotherapy, where radiation must traverse normaltissue in order to reach the tumor, brachytherapy is much more localizedand therefore reduces radiation exposure to normal tissue while allowinga higher radiation dose as compared to external beam radiotherapy.Electrical therapy, as previously discussed may be used in conjunctionwith placement of radioactive sources as is performed in brachytherapy.

In one example, a radioactive source, such as any of cobalt-60,iodine-125, iodine-131, iridium-192, strontium-89 (metastron), andsamarium-153, may be placed on the skin of a patient near a tumor siteor in a patient as a radiation seed. As is known by those of ordinaryskill in the art, radioactive substances may be placed directly in thetissue or organ afflicted with cancer. For example, radiation seeds maybe placed directly in the prostate of those individuals afflicted withprostate cancer.

Electrical therapy may be used in conjunction with hyperthermia therapywherein the temperature of living tissue is increased for therapeuticpurposes. Hyperthermia treatments have for many years been used fortreatment of cancers. It is known that raising of the temperature ofcells to above about 43 degrees Celsius to 45 degrees Celsius for asufficient amount of time causes necrosis, and temperatures below about41.5 degrees Celsius generally do not affect cells. Some types ofmalignant cells reportedly can be destroyed by raising theirtemperatures to levels slightly below those injurious to most normalcells. One of the techniques which has been used for hyperthermia isheating of the blood of a patient by an external apparatus, therebyraising the temperature of the entire body or a portion thereof to thetherapeutic temperature. This procedure risks substantial injury to thepatient if temperature is not carefully controlled, and may fail toraise the temperature of the malignant cells sufficiently fordestruction. Any malignant cells which remain undestroyed may cause arecurrence of the tumor. Therefore, the electrical therapy device asdescribed herein may be used to increase temperature of canceroustissue. Any configuration of leads and electrodes may be used toinnervate cancerous tissue. By strategically placing any number andconfiguration of leads and electrodes in and around cancerous tissue,only cancerous tissue is affected and thus safety in hyperthermiatreatment is increased.

6. CORROSION

In situations where current or voltage is relatively large and/or theduration of the therapy is extended, there may be electrochemicaldegradation (i.e. corrosion) of electrodes over a period of time.However, preventive measures may be taken to lessen any potentialcorrosion. For example, periodic reversals in polarity of electrodesused in electrical therapy are useful to prevent corrosion.Additionally, periodic reversals in DC polarity or pulse polarity inelectrochemotherapy are useful to prevent corrosion. Furthermore, theimplantable device may be configured to be more resistant to corrosionby, for example, including redundant electrodes and utilizing multipleelectrode segments.

Referring to FIG. 45, shown are time varying characteristics of anelectrical pulse used for the purpose of electrical therapy produced bya generator. The abscissa in FIG. 45 represents time, such that a pointnearer to the ordinate is less time and a point further away from theordinate is more time. The ordinate in FIG. 45 represents pulseamplitude, such that a point nearer to the abscissa is a negativeamplitude pulse and a point further away from the abscissa is a positivepulse amplitude.

Shown are positive amplitude portions of the pulse 210, time span ofpositive amplitude portion of the pulse 211, negative amplitude portionof the pulse 212, and time span of negative amplitude portion of thepulse 213.

The generator may be designed so that after a time span of positiveamplitude pulse 211, the positive amplitude portion of the pulse 210switches to the negative amplitude portion of the pulse 212. After atime span of negative amplitude pulse 213, the negative amplitudeportion of the pulse 212 switches back to the positive amplitude portionof the pulse 210, and this pattern repeats indefinitely. The time spanof the positive amplitude portion of the pulse 210, and time span ofnegative amplitude portion of the pulse 213 may or may not be equal inlength. Additionally, the time span of positive amplitude portion of thepulse 210, and time span of negative amplitude portion of the pulse 213may be on the order of minutes to weeks in length.

FIG. 46 illustrates a method of preventing corrosion for use inelectrical therapy. Positive polarity pulse sequences 214 are switchedto negative polarity pulse sequences 215 at the end of time interval216. Negative polarity pulse sequences 215 continue for the duration oftime interval 217. Following time interval 217, negative polarity pulsesequences 215 may be switched back to positive polarity pulse sequences214, as shown in FIG. 46. Time intervals 216 and 217 may be for anylength of time and are not necessarily equal.

In another embodiment, redundant electrodes can be used as is shown inFIG. 47 a-47 b to prevent the adverse effects of corrosion. Shown aretumor 6, redundant electrodes 219 and 220, switch 221, electrodesegments 222 and 223, and lead 224. In FIG. 47 a redundant electrodes219 and 220 are shown inserted into tumor 6. Electrode 219 may be usedin the circuit for a period of time (typically months) and thenelectrode 220 is used in the place of electrode 219 for a second periodof time. Switch 221 is used to switch current between electrodes 219 and220. Any number or type of electrodes may be used in the presentembodiment. In another embodiment sensing the effects of corrosion mayautomatically cause switching from one corroding electrode to the nextuncorroded electrode. The electrodes may be located on separate leads,as shown in FIG. 47 a, or on the same lead, as shown in FIG. 47 b. Lead224 is inserted in tumor 6 and has two electrode segments 222 and 223.

7. EXTERNAL DEVICE

As described herein, the preferred embodiment may be used in conjunctionwith a power source and controlling unit located internally orexternally to a patient. In certain circumstances usage of the externalversion of the preferred embodiment may be advantageous. An externalpower source and controlling unit may be coupled physically and/ortelemetrically to an internal counterpart comprising any combination oflead or leads, electrode or electrodes, internal generator orgenerators, catheter or catheters, port or ports, drug reservoir or drugreservoirs and any other option, feature, and configuration describedpreviously.

A basic form of the external device is illustrated in FIG. 48. Shown arecontrol unit 230, interface wand 231, coupling means 232, leads 233 and234, electrodes 998 and 997, radio frequency communication path 996, andcan 999. Control unit 230 is coupled to interface wand 231 via couplingmeans 232 which may be physical and/or telemetric and includes any of auniversal serial bus (USB), serial port, Personal Computer Memory CardInternational Association (PCMCIA) card, and RF. Interface wand 231 iscoupled to the implantable can 999 via radio frequency communicationpath 996, thereby allowing the electrical therapy system parameters tobe reprogrammed non-invasively. The implantable can 999 is electricallycoupled to leads 233 and 234, which are coupled to electrodes 998 and997. A wide variety of options and features are available for use ineach component.

The control unit may be a computer and in a preferred embodiment is alaptop computer for ease of use and portability. The control unit maycomprise any number of the following programmable features: current(variable or constant), voltage (variable or constant), total charge,time of therapy, polarity selection, and pulse waveforms. Various pulsewaveform parameters may be adjusted such as rate, pulsewidth, frequency,duty cycle, and rounded pulses, which may be advantageously used toincrease patient comfort. The control system may also comprise a displaymonitor and data storage component. Any parameter measured or inputtedto the device may be reflected on a display monitor and recorded in adata storage component. Any of the following parameters may be displayedand/or stored by the device: current, charge, voltage, impedance,temperature, pH, patient information and therapy record, and imaging.Imaging may be used especially in conjunction with IR or an opticallead. The storage component of the device may be a database. In apreferred embodiment, the database information may be displayed in auser friendly form such as graph, pictures, and charts. For example, thechart of FIG. 49 is an example of a user friendly data chart which canbe used to display current information and input changes to thecontroller. Control means of the control system may include any numberof buttons and levers, but may also be adapted to include a foot pedaland/or joystick control. In a preferred embodiment, a joystick controlmay be used to adjust current.

The interface box may be implanted or located external to a patient. Inthe present embodiment, the interface box is located externally to apatient. The interface box may be powered by any combination of isolatedcircuitry, alternating current (AC) line, and battery. The unit may alsobe rechargeable. Electrode outputs may number three or more. At aminimum the outputs should include 2 percutaneous leads and an externalpatch electrode. Additional electrode outputs or adapters may beadvantageously added. For example, electrodes that have selectablecurrent levels such as one-half nominal current or one-fourth nominalcurrent may be used. In a preferred embodiment, these types ofelectrodes may be positioned at the tumor periphery to minimize necrosisof healthy tissue.

The leads and electrodes of the external system may include anycombination of the features, options, and configurations previouslydescribed.

The external device may be used according to the same regimen andtreatment schedule as previously described.

The control system and interface components may be completely externalto the patient or they may be semi-implantable. For example, a receivingcoil with rectifier and lead system may be implanted while the controlsystem and wand are external. Alternatively, a smart semi-implantabledevice with inductive power transfer may be used. In a preferredembodiment the implant has a microprocessor and programming.

8. EXAMPLES

A better understanding of the present embodiment and of its manyadvantages may be clarified with the following examples, given by way ofillustration.

Example 1

Well known for his extensive research and subsequent publications on thetopic of electromedicine, Bjorn Nordenstrom of Sweden developed a theoryon the nature of bio-electricity and the healing process. He treatedcancer in his patients as clinical proof of his theories. His model ofcontrol systems was named “biologically closed electric circuits” (BCEC)and sought to explain structural development in tissue injury andparticularly around cancers. He found that treatment of cancer with DCelectrodes changes the microenvironment of the cancer cells byelectrophoresis of water and fat and electro-osmosis of water. Thetherapy that is based on this principle is called “electrochemicaltreatment” (ECT). His further experimentation showed that direct currentionizes tissue (as does ionizing radiation). Ionization of tissue viadirect electrodes affected normal and malignant tissue differently. Lowenergy levels built up the therapeutic dose of energy from the inside ofthe tumor.

The electrodes used by Nordenstrom were introduced through the chestwall (in the case of lung tumors) into the patient under guidance ofbiplane fluoroscopy or computed tomography under local anesthesia.According to Nordenstrom, the electrodes should present a large surfacearea but should be easily introducible without causing too much damage.

As reported by Nordenstrom in 1978 (Preliminary clinical trials ofelectrophoretic ionization in the treatment of malignant tumors. IRCSMedical Science 6: 537 (1978)), herein incorporated by references,non-operable human lung tumors were treated with DC current. 0.2 mmthick Teflon® insulated platinum electrodes wherein the distal 20 mmwere free from insulation were implanted percutaneously under localanesthesia. One electrode was placed in the tumor and one in thesurrounding tissue or in a vessel supplying the tumor. Ten to 15 volt DCwas then applied with the tumor electropositive. An initial current of 5to 10 mA was then increased gradually to 30 to 40 mA producing intensiveionization. The electropositive tumor tissue turned into a dry gangrenesurrounded by diapedetic bleeding, thrombosis, and intensive leukocyteattraction. The tissue around the electronegative electrode becameedematous by field induced electroosmosis and some minor tissuedestruction and mainly vascular contractions. A gradual decrease in sizeoccurred in the 6 treated tumors at monthly observations.

In addition to the above article, Nordenstrom has other publications ofinterest including Biologically closed electric circuits: Activation ofvascular interstitial closed electric circuits for treatment ofinoperable cancers. Journal of Bioelectricity 3: 137-153 (1984);Biologically Closed Electric Circuits: Clinical, Experimental andTheoretical Evidence for an Additional Circulatory System. Uppsala:Almqvist & Wiksell. (1983); Electrochemical treatment of cancer I:Variable response to anodic and cathodic fields. Am. J. Clin. Oncol. 12:530-536 (1989); Electrochemical treatment of cancer II: Effect ofelectrophoretic influence on adriamycin. Am. J. Clin. Oncol. 13: 75-88(1990) and; Survey of mechanisms in electrochemical treatment (ECT) ofcancer. Eur. J. Surg. Suppl. 574: 93-109 (1994), all of which are hereinincorporated by reference.

Example 2

Habal and Schauble noted in their 1977 paper (An implantable DC powerunit for control of experimental tumor growth in hamsters. MedicalInstrumentation 7: 305-306 (1977)), incorporated herein by reference,that the study of electrometrics in living organisms revealed thepresence of an electropotential difference between non-cancerous organsand tissue and cancerous organs and tissues. Non-cancerous organs werefound to be electropositive in both healthy and tumor-bearing animals,while tumors were found to be electronegative. Human tumors fromsurgical specimens were also found to be more electronegative thannormal tissue.

In their experiment, hamsters with cancerous tumors were treated with acurrent flow of 4.5×10⁻⁹ A. The positive electrode was placed in thecervical region at the tumor injection site, and the negative electrodewas positioned on the dorsum of the hamsters. There was a markeddecrease in tumor volume and the number of metastases in theexperimental group over the positive control group.

In conclusion, the authors hypothesize that a change in the bioelectricmilieu from relative electronegativity to relative electropositivityaffects tumor growth.

Example 3

Xin et al. published the results of treatment of 386 patients withmiddle and late-stage lung cancer in Electrochemical treatment of lungcancer. Bioelectromagnetics 18:8-13 (1997), herein incorporated byreference. According to the therapeutic regimen, cancerous tumors weretreated with a voltage of 6-8 V, a current of 80-100 mA, and an electriccharge of 100 coulombs per cm of tumor diameter via anode and cathodeplatinum electrodes which were inserted transcutaneously orintraoperatively into the tumor mass. Generally, anodes were placed inthe tumor center and cathodes in the tumor periphery less than 2 cm fromthe tumor boundary in order to protect the normal (non-cancerous) tissuefrom electrical damage, edema, and chemical changes produced by thereaction near the cathodes. The short term effective rate was 72% (278cases) and the 5 year survival rate was 29.5%.

The authors comment that the effect of ECT with lower current (40-60 mA)and longer duration (2-2.5 hours) is better than that of ECT with highercurrent (100-150 mA) and shorter duration (1-1.5 hours). Generally, theauthors found that 4 V and 20 mA are the minimal limit for ECT.Experimental results showed that about 100 coulombs per 1 cm of diameterof tumor tissue are needed for cytotoxicity. Cicatricial tumor tissue,which has fewer electrolytes, was found to need more electricity.Alternatively, squamous cell carcinomas, which contain more electrolytesthan cicatricial tumor tissue, needed a lower amount of electricity.Additionally, the authors comment that based on their experimentation,placing both anodes and cathodes into tumors with anodes in the centerand cathodes on the periphery works to protect normal (non canceroustissue) and enhances the therapeutic effect. The authors also found thatthe cytotoxic diameter around each electrode is about 3 cm. Thus, thedistance between electrodes should not exceed 3 cm and the number ofelectrodes should be determined based on the tumor size and shape.

Other relevant articles by Xin et al. include Effectiveness ofelectrochemical therapy in the treatment of lung cancers of middle andlate stage. Chinese Medical Journal 110: 379-383 (1997) and Organizationand spread of electrochemical therapy (ECT) in China. Eur. J. Surg.Suppl. 577:25-30 (1994), which are herein incorporated by reference.

Example 4

In a paper by Li et al. results of ECT on dog liver were reported(Effects of direct current on dog liver: Possible mechanisms for tumorelectrochemical treatment. Bioelectromagnetics 18:2-7 (1997)).Mechanisms of tumor electrochemical treatment (ECT) were studied usingnormal dog liver. Five physical and chemical methods were used. Twoplatinum electrodes were inserted into an anesthetized dog's liver at 3cm separation. A voltage of 8.5 V DC current at an average current of 30mA was applied for 69 minutes; total charge was 124 coulombs.Concentrations of selected ions near the anode and cathode weremeasured. The concentrations of Na⁺ and K⁺ ions were higher around thecathode, whereas the concentration of Cl⁻ ions was higher around theanode. Water contents and pH were determined near the anode and cathodeat the midpoint between the two electrodes and in an untreated area awayfrom the electrodes. Hydration occurred around the cathode, anddehydration occurred around the anode. The pH values were 2.1 near theanode and 12.9 near the cathode. Spectrophotometric scans of the liversample extract were obtained, and the released gases were identified bygas chromatography as chlorine at the anode and hydrogen at the cathode.These results indicate that a series of electrochemical reactions takeplace during ECT. The cell metabolism and its environment are severelydisturbed. Both normal and tumor cells are rapidly and completelydestroyed in this altered environment. In conclusion, the authorshypothesize that the above reactions are the ECT mechanisms responsiblefor treating tumors.

Example 5

In a paper by Orlowski et al. (Transient electropermeabilization ofcells in culture: Increase of the cytotoxicity of anticancer drugs.Biochemical Pharmacology 37:4727-4733 (1988)), herein incorporated byreference, effectiveness of anticancer drugs was tested in conjunctionwith electroporation. According to Orlowski, electropermeabilization(EPN) of living cells allows the uptake of non-permanent molecules andcan reveal the drugs' potential activity on cells without theconstraints of the plasma membrane crossing. In their experiment theycompared the cytotoxicity of some anticancer drugs onelecropermeabilized (EP) and non-permeabilized (NEP) cultured DC-3Fcells exposed to the drugs for a short time. After EPN, the increase incytotoxicity varied between 1 and more than 700 times, depending on theusual cell uptake pathway of a given drug. The most relevant increase oftoxicity was observed with molecules such as netropsin (200-fold) andbleomycin (700-fold) which in ordinary conditions weakly diffuse throughthe plasma membrane. Only a 3-5 fold increase of cytotoxicity wasobserved with lipophilic drugs able to rapidly diffuse through theplasma membrane (actinomycin D, NMHE) both in the case of drug-sensitiveand resistant cell strains. This increased toxicity is clearly relatedto a facilitated uptake because, after electropermeabilization, theeffects of melphalan (a drug which enters intact cells via leucinetransporters) are not modulated by the external leucine concentration.In conclusion, the authors propose that uptake of anti-cancer and othercytotoxic drugs can be modified by EPN.

All references cited herein are incorporated by reference.

1. A method for the treatment of abnormal tissue growth madeup ofabnormal cells, the method comprising: providing circuitry coupled to apower source; providing at least one electrode operably coupled to saidcircuitry; and delivering through said circuitry direct currentelectrical therapy as a series of voltage pulses between 20 and 900volts for ablating at least one abnormal cell and simultaneously causingelectroporation of at least one abnormal cell; wherein said electricaltherapy is delivered at a duty cycle in the range of 50 to 70 percent.2. The method of claim 1 wherein said direct current electrical therapyis applied at voltages and time periods sufficient for changing the pHby at least 2.0 inside said abnormal tissue growth.
 3. The method ofclaim 1 wherein said direct current electrical therapy is applied for aperiod of time not less than 1 minute.
 4. The method of claim 1 whereinsaid direct current electrical therapy is delivered in pulses numberingbetween 1 and 10,000.